Substituted isoindolones and their use as metabotropic glutamate receptor potentiators

ABSTRACT

The present invention is directed to compounds of formula I: 
                         
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9  and n are as defined for formula I in the description. The invention also relates to processes for the preparation of the compounds and to new intermediates employed in the preparation, pharmaceutical compositions containing the compounds, and to the use of the compounds in therapy.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation-In-Part of PCT ApplicationPCT/US05/28760, filed Aug. 12, 2005, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

The present invention relates to novel compounds that function aspotentiators of glutamate receptors, methods for their preparation,pharmaceutical compositions containing them and their use in therapy.

The metabotropic glutamate receptors (mGluR) constitute a family ofGTP-binding-protein (G-protein) coupled receptors that are activated byglutamate, and have important roles in synaptic activity in the centralnervous system, including neural plasticity, neural development andneurodegeneration.

Activation of mGluRs in intact mammalian neurons elicits one or more ofthe following responses: activation of phospholipase C; increases inphosphoinositide (PI) hydrolysis; intracellular calcium release;activation of phospholipase D; activation or inhibition of adenylcyclase; increases or decreases in the formation of cyclic adenosinemonophosphate (cAMP); activation of guanylyl cyclase; increases in theformation of cyclic guanosine monophosphate (cGMP); activation ofphospholipase A₂; increases in arachidonic acid release; and increasesor decreases in the activity of voltage- and ligand-gated ion channels(Schoepp et al., 1993, Trends Pharmacol. Sci., 14:13; Schoepp, 1994,Neurochem. Int., 24:439; Pin et al., 1995, Neuropharmacology 34:1; Bordi& Ugolini, 1999, Prog. Neurobiol. 59:55).

Eight mGluR subtypes have been identified, which are divided into threegroups based upon primary sequence similarity, signal transductionlinkages, and pharmacological profile. Group-I includes mGluR1 andmGluR5, which activate phospholipase C and the generation of anintracellular calcium signal. The Group-II (mGluR2 and mGluR3) andGroup-III (mGluR4, mGluR6, mGluR7, and mGluR8) mGluRs mediate aninhibition of adenylyl cyclase activity and cyclic AMP levels. For areview, see Pin et al., 1999, Eur. J. Pharmacol., 375:277-294.

Activity of mGluR family receptors are implicated in a number of normalprocesses in the mammalian CNS, and are important targets for compoundsfor the treatment of a variety of neurological and psychiatricdisorders. Activation of mGluRs is required for induction of hippocampallong-term potentiation and cerebellar long-term depression (Bashir etal., 1993, Nature, 363:347; Bortolotto et al., 1994, Nature, 368:740;Aiba et al., 1994, Cell, 79:365 Aiba et al., 1994, Cell, 79:377). A rolefor mGluR activation in nociception and analgesia also has beendemonstrated (Meller et al., 1993, Neuroreport, 4: 879; Bordi & Ugolini,1999, Brain Res., 871:223). In addition, mGluR activation has beensuggested to play a modulatory role in a variety of other normalprocesses including synaptic transmission, neuronal development,apoptotic neuronal death, synaptic plasticity, spatial learning,olfactory memory, central control of cardiac activity, waking, motorcontrol and control of the vestibulo-ocular reflex (Nakanishi, 1994,Neuron, 13:1031; Pin et al., 1995, Neuropharmacology, supra; Knopfel etal., 1995, J. Med. Chem., 38:1417).

Recent advances in the elucidation of the neurophysiological roles ofmGluRs have established these receptors as promising drug targets in thetherapy of acute and chronic neurological and psychiatric disorders andchronic and acute pain disorders. Because of the physiological andpathophysiological significance of the mGluRs, there is a need for newdrugs and compounds that can modulate mGluR function.

SUMMARY OF THE INVENTION

We have identified a class of compounds that modulate mGluR function. Inone aspect the invention provides compounds of formula I,

wherein:

-   R¹ is a 3- to 7-membered ring that may contain one or more    heteroatoms independently selected from the group consisting of N, O    and S, wherein said ring may be substituted by one or more A;-   R² and R³ are independently selected from the group consisting of H,    C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, aryl, heteroaryl,    heterocycloalkyl, C₃₋₈-cycloalkyl, C₁₋₆-alkyl-aryl,    C₁₋₆-alkylheteroaryl, C₁₋₆-alkyl-heterocycloalkyl, and    C₁₋₆-alkyl-C₃₋₈-cycloalkyl, wherein R² and R³ may be substituted by    one or more A;-   R⁴ and R⁶ are independently selected from the group consisting of H,    hydroxy, F, Cl, Br, I, nitro, cyano, C₁₋₆-alkyl, C₁₋₆-alkylhalo,    OC₁₋₆alkyl, OC₁₋₆-alkylhalo, C₂₋₆-alkenyl, OC₂₋₆-alkenyl,    C₂₋₆-alkynyl, OC₂₋₆-alkynyl, C₃₋₈-cycloalkyl,    C₁₋₆-alkyl-C₃₋₈-cycloalkyl, OC₀₋₆-alkyl-C₃₋₈-cycloalkyl, aryl,    C₁₋₆-alkylaryl, OC₀₋₆-alkylaryl, (CO)R¹⁰, O(CO)R¹⁰, O(CO)OR¹⁰,    C(O)OR¹⁰, O(CNR¹⁰)OR¹¹, C₁₋₆-alkylOR¹⁰, OC₂₋₆-alkylOR¹⁰,    C₁₋₆-alkyl(CO)R¹⁰, OC₁₋₆-alkyl(CO)R¹⁰, C₀₋₆-alkylCO₂R¹⁰,    OC₁₋₆-alkylCO₂R¹⁰, C₁₋₆-alkylcyano, OC₂₋₆-alkylcyano,    C₀₋₆-alkylNR¹⁰R¹¹, OC₂₋₆-alkylNR¹⁰R¹¹, C₁₋₆-alkyl(CO)NR¹⁰R¹¹,    OC₀₋₆-alkyl(CO)NR¹⁰R¹¹, C₀₋₆-alkylNR¹⁰(CO)R¹¹,    OC₂₋₆-alkylNR¹⁰(CO)R¹¹, C₀₋₆-alkylNR¹⁰(CO)NR¹⁰R¹¹, C₀₋₆-alkylSR¹⁰,    OC₂₋₆-alkylSR¹⁰, C₀₋₆-alkyl(SO)R¹⁰, OC₂₋₆-alkyl(SO)R¹⁰,    C₁₋₆-alkylSO₂R¹⁰, OC₂₋₆-alkylSO₂R¹⁰, C₀₋₆-alkyl(SO₂)NR¹⁰R¹¹,    OC₂₋₆-alkyl(SO₂)NR¹⁰R¹¹, C₀₋₆-alkylNR¹⁰(SO₂)R¹¹,    OC₂₋₆-alkylNR¹⁰(SO₂)R¹¹, C₀₋₆-alkylNR¹⁰(SO₂)NR¹⁰R¹¹,    OC₂₋₆-alkylNR¹⁰(SO₂)NR¹⁰R¹¹, (CO)NR¹⁰R¹¹, O(CO)NR¹⁰R¹¹, NR¹⁰OR¹¹,    C₀₋₆-alkylNR¹⁰(CO)OR¹¹, OC₂₋₆-alkylNR¹⁰(CO)OR¹¹, SO₃R¹⁰ and a 5- to    7-membered ring that may contain one or more heteroatoms    independently selected from the group consisting of N, O and S,    wherein R⁴ and R⁶ may be substituted by one or more A, and wherein    any cycloalkyl or aryl is optionally fused to a 5- to 7-membered    ring that may contain one or more heteroatoms independently selected    from the group consisting of C, N, O and S;-   R⁵ is selected from the group consisting of CN, OC₀₋₆-alkyl,    C₃₋₈-cycloalkyl, C₁₋₆-alkyl-C₃₋₈-cycloalkyl,    OC₀₋₆-alkyl-C₃₋₈-cycloalkyl, C₀₋₆-alkylaryl, OC₀₋₆-alkylaryl,    C₀₋₆-alkylheteroaryl, OC₀₋₆-alkylheteroaryl, heterocycloalkyl,    C₁₋₆-alkylheterocycloalkyl, OC₀₋₆-alkylheterocycloalkyl and C(O)R₁₀,    wherein any cyclic moiety is substituted by one or more B;-   R⁷ is selected from the group consisting of H, F, Cl, Br, I, nitro,    cyano, OC₁₋₄-alkyl, C₁₋₆-alkyl, C₁₋₆-alkylhalo, OC₁₋₆-alkylhalo,    C₂₋₆-alkenyl, OC₂₋₆-alkenyl, C₂₋₆-alkynyl, OC₂₋₆-alkynyl, and    C₃₋₈-cycloalkyl;-   R⁸ and R⁹ are independently selected from the group consisting of H,    F, Cl, Br, I, nitro, cyano, C₁₋₆-alkyl, C₁₋₆-alkylhalo, OC₁₋₆alkyl,    OC₁₋₆-alkylhalo, C₂₋₆-alkenyl, OC₂₋₆-alkenyl, C₂₋₆-alkynyl, and    OC₂₋₆-alkynyl,    or, where n is greater than 1,    two or more R⁸ and/or R⁹ on adjacent carbon atoms may be absent to    form an alkenyl or alkynyl moiety;-   R¹⁰ and R¹¹ are independently selected from the group consisting of    H, hydroxy, oxo, F, Cl, Br, I, nitro, cyano, C₁₋₆-alkyl,    C₁₋₆-alkylhalo, OC₁₋₆alkyl, OC₁₋₆-alkylhalo, C₂₋₆-alkenyl,    OC₂₋₆-alkenyl, C₂₋₆-alkynyl, OC₂₋₆-alkynyl, C₃₋₈-cycloalkyl,    C₁₋₆-alkyl-C₃₋₈-cycloalkyl, OC₀₋₆-alkyl-C₃₋₈-cycloalkyl, aryl,    C₁₋₆-alkylaryl, OC₀₋₆-alkylaryl, C₀₋₆-alkyl-heterocycloalkyl,    OC₁₋₆-alkyl-heterocycloalkyl, heteroaryl, C₁₋₆alkylheteroaryl,    heterocycloalkyl-C₁₋₆-alkylaryl and    heterocycloalkyl-C₁₋₆-alkylheteroaryl, wherein any cyclic moiety is    optionally fused to a 5- to 7-membered ring that may contain one or    more heteroatoms independently selected from the group consisting of    C, N, O and S and any cyclic moiety is optionally substituted with a    substituent selected from alkyl, halo, hydroxyl, Oalkyl, haloalkyl    and Ohaloalkyl;-   A is selected from the group consisting of H, hydroxy, F, Cl, Br, I,    nitro, cyano, oxo, C₁₋₆-alkyl, C₁₋₆-alkylhalo, OC₁₋₆alkyl,    OC₁₋₆-alkylhalo, C₂₋₆-alkenyl, OC₂₋₆-alkenyl, C₂₋₆-alkynyl,    OC₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₁₋₆-alkyl-C₃₋₈-cycloalkyl,    OC₀₋₆-alkyl-C₃₋₈-cycloalkyl, aryl, C₁₋₆-alkylaryl, OC₀₋₆-alkylaryl,    C₁₋₆-alkyl-heterocyclyl, C₁₋₆-alkyl-heterocycloalkyl,    OC₀₋₆-alkyl-heterocycloalkyl, (CO)R¹⁰, O(CO)R¹⁰, O(CO)OR¹⁰,    O(CNR¹⁰)OR¹¹, C₁₋₆-alkylOR¹⁰, OC₂₋₆-alkylOR¹⁰, C₁₋₆-alkyl(CO)R¹⁰,    OC₁₋₆-alkyl(CO)R¹⁰, C₀₋₆-alkylCO₂R¹⁰, OC₁₋₆-alkylCO₂R¹⁰,    C₁₋₆-alkylcyano, OC₂₋₆-alkylcyano, C₀₋₆-alkylNR¹⁰R¹¹,    OC₂₋₆-alkylNR¹⁰R¹¹, C₀₋₆-alkyl(CO)NR¹⁰R¹¹, OC₁₋₆-alkyl(CO)NR¹⁰R¹¹,    C₀₋₆-alkylNR¹⁰(CO)R¹¹, OC₂₋₆-alkylNR¹⁰(CO)R¹¹,    C₀₋₆-alkylNR¹⁰(CO)NR¹⁰R¹¹, C₀₋₆-alkylSR¹⁰, OC₂₋₆-alkylSR¹⁰,    C₀₋₆-alkyl(SO)R¹⁰, OC₂₋₆-alkyl(SO)R¹⁰, C₁₋₆-alkylSO₂R¹⁰,    OC₂₋₆-alkylSO₂R¹⁰, C₀₋₆-alkyl(SO₂)NR¹⁰R¹¹, OC₂₋₆-alkyl(SO₂)NR¹⁰R¹¹,    C₀₋₆-alkylNR¹⁰(SO₂)R¹¹, OC₂₋₆-alkylNR¹⁰(SO₂)R¹¹,    C₀₋₆-alkylNR¹⁰(SO₂)NR¹⁰R¹¹, OC₂₋₆-alkylNR¹⁰(SO₂)NR¹⁰R¹¹,    (CO)NR¹⁰R¹¹, O(CO)NR¹⁰R¹¹, NR¹⁰OR¹¹, C₀₋₆-alkylNR¹⁰(CO)OR¹¹,    OC₂₋₆-alkylNR¹⁰(CO)OR¹¹, SO₃R¹⁰ and a 5- to 7-membered ring that may    contain one or more heteroatoms independently selected from the    group consisting of N, O and S, wherein said 5- to 7-membered ring    is optionally substituted by one or more of R¹⁰ and R¹¹;-   B is selected from the group consisting of    C₀₋₆-alkyl-C₃₋₈-cycloalkyl, OC₀₋₆-alkyl-C₃₋₈-cycloalkyl,    C₀₋₆-alkylaryl, OC₀₋₆-alkylaryl, C₁₋₆-alkylheterocycloalkyl, OC₀₋₆    alkylheterocycloalkyl, C₁₋₆-alkylheteroaryl and    OC₁₋₆-alkylheteroaryl, wherein any cyclic moiety is substituted with    at least one substituent selected from the group consisting of halo,    alkyl alkylhalo, alkoxy, oxo, COR, CO₂R, SO₂R and CN;-   R is selected from the group consisting of H and alkyl;-   and-   n is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and    8;-   or a pharmaceutically acceptable salt, hydrate, solvate, optical    isomer, or combination thereof.

The invention also provides processes for the preparation of compoundsof formula I.

The invention further provides a pharmaceutical composition comprising acompound according to formula I together with a pharmaceuticallyacceptable carrier or excipient; in another aspect the inventionprovides a method for the treatment or prevention of neurological andpsychiatric disorders associated with glutamate dysfunction in an animalin need of such treatment. The method comprises the step ofadministering to the animal a therapeutically effective amount of acompound of formula I or a pharmaceutical composition thereof.

The invention also provides for the use of a compound according toformula I, or a pharmaceutically acceptable salt or solvate thereof inthe manufacture of a medicament for the treatment of any of theconditions discussed herein. Further, the invention provides a compoundof formula I, or a pharmaceutically acceptable salt or solvate thereof,for use in therapy.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is based upon the discovery of compounds thatexhibit activity as pharmaceuticals, in particular as modulators ofmetabotropic glutamate receptors. More particularly, the compounds ofthe present invention exhibit activity as potentiators of the mGluR2receptor, and are useful in therapy, in particular for the treatment ofneurological and psychiatric disorders associated with glutamatedysfunction.

Definitions

Unless specified otherwise within this specification, the nomenclatureused in this specification generally follows the examples and rulesstated in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F,and H, Pergamon Press, Oxford, 1979, which is incorporated by referencesherein for its exemplary chemical structure names and rules on namingchemical structures. Optionally, a name of a compound may be generatedusing a chemical naming program: ACD/ChemSketch, Version 5.09/September2001, Advanced Chemistry Development, Inc., Toronto, Canada.

The term “alkyl” as used herein means a straight- or branched-chainhydrocarbon radical having, for example, from one to six carbon atoms,and includes methyl)ethyl, propyl, isopropyl, t-butyl and the like.

The term “alkenyl” as used herein means a straight- or branched-chainalkenyl radical having, for example, from two to six carbon atoms, andincludes ethenyl, 1-propenyl, 1-butenyl and the like.

The term “alkynyl” as used herein means a straight- or branched-chainalkynyl radical having, for example, from two to six carbon atoms, andincludes 1-propynyl (propargyl), 1-butynyl and the like.

The term “cycloalkyl” as used herein means a cyclic group (which may beunsaturated) having, for example, from three to seven carbon atoms, andincludes cyclopropyl, cyclohexyl, cyclohexenyl and the like.

The term “heterocycloalkyl” as used herein means, for example, a three-to seven-membered cyclic group (which may be unsaturated) having atleast one heteroatom selected from the group consisting of N, S and O,and includes piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyland the like.

The term “alkoxy” as used herein means a straight- or branched-chainalkoxy radical having, for example, from one to six carbon atoms andincludes methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and thelike.

The term “halo” as used herein means halogen and includes fluoro,chloro, bromo, iodo and the like, in both radioactive andnon-radioactive forms.

The term “aryl” as used herein means an aromatic group having, forexample, five to twelve atoms, and includes phenyl, naphthyl and thelike.

The term “heteroaryl” means an aromatic group which includes at leastone heteroatom selected from the group consisting of N, S and O, andincludes groups and includes pyridyl, indolyl, furyl, benzofuryl,thienyl, benzothienyl, quinolyl, oxazolyl and the like.

The term “alkanoyl” as used herein means a straight- or branched-chainalkanoyl radical having, for example, from two to seven atoms, andincludes acetyl, propionyl, butyryl and the like.

The term “cycloalkenyl” as used herein means an unsaturated cycloalkylgroup having, for example, from four to seven carbon atoms, and includescyclopent-1-enyl, cyclohex-1-enyl and the like.

The terms “alkylaryl”, “alkylheteroaryl” and “alkylcycloalkyl” refer toan alkyl radical substituted with an aryl, heteroaryl or cycloalkylgroup, and includes 2-phenethyl, 3-cyclohexyl propyl and the like.

The term “5- to 7-membered ring that may contain one or more heteroatomsindependently selected from N, O and S” includes aromatic andheteroaromatic rings, as well as carbocyclic and heterocyclic ringswhich may be saturated or unsaturated, and includes furyl, isoxazolyl,oxazolyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl,thiazolyl, thienyl, imidazolyl, triazolyl, morpholinyl, piperazinyl,piperidinyl, homopiperidinyl, tetrahydropyranyl, phenyl, cyclohexyl,cycloheptyl, cyclopentyl, cyclohexanyl and the like.

The term “pharmaceutically acceptable salt” means either an acidaddition salt or a basic addition salt which is compatible with thetreatment of patients.

A “pharmaceutically acceptable acid addition salt” is any non-toxicorganic or inorganic acid addition salt of the base compoundsrepresented by Formula I or any of its intermediates. Illustrativeinorganic acids which form suitable salts include hydrochloric,hydrobromic, sulfuric and phosphoric acid and acid metal salts such assodium monohydrogen orthophosphate and potassium hydrogen sulfate.Illustrative organic acids which form suitable salts include the mono-,di- and tricarboxylic acids. Illustrative of such acids are, forexample, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric,fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic,benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic,2-phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids suchas methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either themono- or di-acid salts can be formed, and such salts can exist in eithera hydrated, solvated or substantially anhydrous form. In general, theacid addition salts of these compounds are more soluble in water andvarious hydrophilic organic solvents, and generally demonstrate highermelting points in comparison to their free base forms. The selectioncriteria for the appropriate salt will be known to one skilled in theart. Other non-pharmaceutically acceptable salts e.g. oxalates may beused for example in the isolation of compounds of Formula I forlaboratory use, or for subsequent conversion to a pharmaceuticallyacceptable acid addition salt.

A “pharmaceutically acceptable basic addition salt” is any non-toxicorganic or inorganic base addition salt of the acid compoundsrepresented by Formula I or any of its intermediates. Illustrativeinorganic bases which form suitable salts include lithium, sodium,potassium, calcium, magnesium or barium hydroxides. Illustrative organicbases which form suitable salts include aliphatic, alicyclic or aromaticorganic amines such as methylamine, trimethyl amine and picoline orammonia. The selection of the appropriate salt may be important so thatan ester functionality, if any, elsewhere in the molecule is nothydrolyzed. The selection criteria for the appropriate salt will beknown to one skilled in the art.

“Solvate” means a compound of Formula I or the pharmaceuticallyacceptable salt of a compound of Formula I wherein molecules of asuitable solvent are incorporated in a crystal lattice. A suitablesolvent is physiologically tolerable at the dosage administered as thesolvate. Examples of suitable solvents are ethanol, water and the like.When water is the solvent, the molecule is referred to as a hydrate.

The term “stereoisomers” is a general term for all isomers of theindividual molecules that differ only in the orientation of their atomsin space. It includes mirror image isomers (enantiomers), geometric(cis/trans) isomers and isomers of compounds with more than one chiralcentre that are not mirror images of one another (diastereomers).

The term “treat” or “treating” means to alleviate symptoms, eliminatethe causation of the symptoms either on a temporary or permanent basis,or to prevent or slow the appearance of symptoms of the named disorderor condition.

The term “therapeutically effective amount” means an amount of thecompound which is effective in treating the named disorder or condition.

The term “pharmaceutically acceptable carrier” means a non-toxicsolvent, dispersant, excipient, adjuvant or other material which ismixed with the active ingredient in order to permit the formation of apharmaceutical composition, i.e., a dosage form capable ofadministration to the patient. One example of such a carrier is apharmaceutically acceptable oil typically used for parenteraladministration.

Compounds

Compounds of the invention conform generally to formula I:

wherein:

-   R¹ is a 3- to 7-membered ring that may contain one or more    heteroatoms independently selected from the group consisting of N, O    and S, wherein said ring may be substituted by one or more A;-   R² and R³ are independently selected from the group consisting of H,    C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, aryl, heteroaryl,    heterocycloalkyl, C₃₋₈-cycloalkyl, C₁₋₆-alkyl-aryl,    C₁₋₆-alkyl-heteroaryl, C₁₋₆-alkyl-heterocycloalkyl, and    C₁₋₆-alkyl-C₃₋₈-cycloalkyl, wherein R² and R³ may be substituted by    one or more A;-   R⁴ and R⁶ are independently selected from the group consisting of H,    hydroxy, F, Cl, Br, I, nitro, cyano, C₁₋₆-alkyl, C₁₋₆-alkylhalo,    OC₁₋₆alkyl, OC₁₋₆-alkylhalo, C₂₋₆-alkenyl, OC₂₋₆-alkenyl,    C₂₋₆-alkynyl, OC₂₋₆-alkynyl, C₃₋₈-cycloalkyl,    C₁₋₆-alkyl-C₃₋₈-cycloalkyl, OC₀₋₆-alkyl-C₃₋₈-cycloalkyl, aryl,    C₁₋₆-alkylaryl, OC₀₋₆-alkylaryl, (CO)R¹⁰, O(CO)R¹⁰, O(CO)OR¹⁰,    C(O)OR¹⁰, O(CNR¹⁰)OR¹¹, C₁₋₆-alkylOR¹⁰, OC₂₋₆-alkylOR¹⁰,    C₁₋₆-alkyl(CO)R¹⁰, OC₁₋₆-alkyl(CO)R¹⁰, C₀₋₆-alkylCO₂R¹⁰,    OC₁₋₆-alkylCO₂R¹⁰, C₁₋₆-alkylcyano, OC₂₋₆-alkylcyano,    C₀₋₆-alkylNR¹⁰R¹¹, OC₂₋₆-alkylNR¹⁰R¹¹, C₁₋₆-alkyl(CO)NR¹⁰R¹¹,    OC₁₋₆-alkyl(CO)NR¹⁰R¹¹, C₀₋₆-alkylNR¹⁰(CO)R¹¹,    OC₂₋₆-alkylNR¹⁰(CO)R¹¹, C₀₋₆-alkylNR¹⁰(CO)NR¹⁰R¹¹, C₀₋₆-alkylSR¹⁰,    OC₂₋₆-alkylSR¹⁰, C₀₋₆-alkyl(SO)R¹⁰, OC₂₋₆-alkyl(SO)R¹⁰,    C₀₋₆-alkylSO₂R¹⁰, OC₂₋₆-alkylSO₂R¹⁰, C₀₋₆-alkyl(SO₂)NR¹⁰R¹¹,    OC₂₋₆-alkyl(SO₂)NR¹⁰R¹¹, C₀₋₆-alkylNR¹⁰(SO₂)R¹¹,    OC₂₋₆-alkylNR¹⁰(SO₂)R¹¹, C₀₋₆-alkylNR¹⁰(SO₂)NR¹⁰R¹¹,    OC₂₋₆-alkylNR¹⁰(SO₂)NR¹⁰R¹¹, (CO)NR¹⁰R¹¹, O(CO)NR¹⁰R¹¹, NR¹⁰OR¹¹,    C₀₋₆-alkylNR¹⁰(CO)OR¹¹, OC₂₋₆-alkylNR¹⁰(CO)OR¹¹, SO₃R¹⁰ and a 5- to    7-membered ring that may contain one or more heteroatoms    independently selected from the group consisting of N, O and S,    wherein R⁴ and R⁶ may be substituted by one or more A, and wherein    any cycloalkyl or aryl is optionally fused to a 5- to 7-membered    ring that may contain one or more heteroatoms independently selected    from the group consisting of C, N, O and S;-   R⁵ is selected from the group consisting of CN, OC₀₋₆-alkyl,    C₃₋₈-cycloalkyl, C₁₋₆-alkyl-C₃₋₈-cycloalkyl,    OC₀₋₆-alkyl-C₃₋₈-cycloalkyl, C₀₋₆-alkylaryl, OC₀₋₆-alkylaryl,    C₀₋₆-alkylheteroaryl, OC₀₋₆-alkylheteroaryl, heterocycloalkyl,    C₁₋₆-alkylheterocycloalkyl, OC₀₋₆-alkylheterocycloalkyl and C(O)R¹⁰,    wherein any cyclic moiety is substituted by one or more B;-   R⁷ is selected from the group consisting of H, F, Cl, Br, I, nitro,    cyano, OC₁₋₄-alkyl, C₁₋₆-alkyl, C₁₋₆-alkylhalo, OC₁₋₆-alkylhalo,    C₂₋₆-alkenyl, OC₂₋₆-alkenyl, C₂₋₆-alkynyl, OC₂₋₆-alkynyl, and    C₃₋₈-cycloalkyl;-   R⁸ and R⁹ are independently selected from the group consisting of H,    F, Cl, Br, I, nitro, cyano, C₁₋₆-alkyl, C₁₋₆-alkylhalo, OC₁₋₆-alkyl,    OC₁₋₆-alkylhalo, C₂₋₆-alkenyl, OC₂₋₆-alkenyl, C₂₋₆-alkynyl, and    OC₂₋₆-alkynyl,-   or, where n is greater than 1,-   two or more R⁸ and/or R⁹ on adjacent carbon atoms may be absent to    form an alkenyl or alkynyl moiety;-   R¹⁰ and R¹¹ are independently selected from the group consisting of    H, hydroxy, oxo, F, Cl, Br, I, nitro, cyano, C₁₋₆-alkyl,    C₁₋₆-alkylhalo, OC₁₋₆alkyl, OC₁₋₆-alkylhalo, C₂₋₆-alkenyl,    OC₂₋₆-alkenyl, C₂₋₆-alkynyl, OC₂₋₆-alkynyl, C₃₋₈-cycloalkyl,    C₁₋₆-alkyl-C₃₋₈-cycloalkyl, OC₀₋₆-alkyl-C₃₋₈-cycloalkyl, aryl,    C₁₋₆-alkylaryl, OC₀₋₆-alkylaryl, C₀₋₆-alkyl-heterocycloalkyl,    OC₁₋₆-alkyl-heterocycloalkyl, heteroaryl, C₁₋₆alkylheteroaryl,    heterocycloalkyl-C₁₋₆-alkylaryl and    heterocycloalkyl-C₁₋₆-alkylheteroaryl, wherein any cyclic moiety is    optionally fused to a 5- to 7-membered ring that may contain one or    more heteroatoms independently selected from the group consisting of    C, N, O and S and any cyclic moiety is optionally substituted with a    substituent selected from alkyl, halo, hydroxyl, Oalkyl, haloalkyl    and Ohaloalkyl;-   A is selected from the group consisting of H, hydroxy, F, Cl, Br, I,    nitro, cyano, oxo, C₁₋₆-alkyl, C₁₋₆-alkylhalo, OC₁₋₆alkyl,    OC₁₋₆-alkylhalo, C₂₋₆-alkenyl, OC₂₋₆-alkenyl, C₂₋₆-alkynyl,    OC₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₁₋₆-alkyl-C₃₋₈-cycloalkyl,    OC₀₋₆-alkyl-C₃₋₈-cycloalkyl, aryl, C₁₋₆-alkylaryl, OC₀₋₆-alkylaryl,    C₁₋₆-alkyl-heterocyclyl, C₁₋₆-alkyl-heterocycloalkyl,    OC₀₋₆-alkyl-heterocycloalkyl, (CO)R¹⁰, O(CO)R¹⁰, O(CO)OR¹⁰,    O(CNR¹⁰)OR¹¹, C₁₋₆-alkylOR¹⁰, OC₂₋₆-alkylOR¹⁰, C₁₋₆-alkyl(CO)R¹⁰,    OC₁₋₆-alkyl(CO)R¹⁰, C₀₋₆-alkylCO₂R¹⁰, OC₁₋₆-alkylCO₂R¹⁰,    C₁₋₆-alkylcyano, OC₂₋₆-alkylcyano, C₀₋₆-alkylNR¹⁰R¹¹,    OC₂₋₆-alkylNR¹⁰R¹¹, C₀₋₆-alkyl(CO)NR¹⁰R¹¹, OC₁₋₆-alkyl(CO)NR¹⁰R¹¹,    C₀₋₆-alkylNR¹⁰(CO)R¹¹, OC₂₋₆-alkylNR¹⁰(CO)R¹¹,    C₀₋₆-alkylNR¹⁰(CO)NR¹⁰R¹¹, C₀₋₆-alkylSR¹⁰, OC₂₋₆-alkylSR¹⁰,    C₀₋₆-alkyl(SO)R¹⁰), OC₂₋₆-alkyl(SO)R¹⁰, C₁₋₆-alkylSO₂R¹⁰,    OC₂₋₆-alkylSO₂R¹⁰, C₀₋₆-alkyl(SO₂)NR¹⁰R¹¹, OC₂₋₆-alkyl(SO₂)NR¹⁰R¹¹,    C₀₋₆-alkylNR¹⁰(SO₂)R¹¹, OC₂₋₆-alkylNR¹⁰(SO₂)R¹¹,    C₀₋₆-alkylNR¹⁰(SO₂)NR¹⁰R¹¹, OC₂₋₆-alkylNR¹⁰(SO₂)NR¹⁰R¹¹,    (CO)NR¹⁰R¹¹, O(CO)NR¹⁰R¹¹, NR¹⁰OR¹¹, C₀₋₆-alkylNR¹⁰(CO)OR¹¹,    OC₂₋₆-alkylNR¹⁰(CO)OR¹¹, SO₃R¹⁰ and a 5- to 7-membered ring that may    contain one or more heteroatoms independently selected from the    group consisting of N, O and S, wherein said 5- to 7-membered ring    is optionally substituted by one or more of R¹⁰ and R¹¹;-   B is selected from the group consisting of    C₀₋₆-alkyl-C₃₋₈-cycloalkyl, OC₀₋₆-alkyl-C₃₋₈-cycloalkyl,    C₀₋₆-alkylaryl, OC₀₋₆-alkylaryl, C₁₋₆-alkylheterocycloalkyl,    OC₀₋₆-alkylheterocycloalkyl, C₁₋₆-alkylheteroaryl and    C₁₋₆-alkylheteroaryl, wherein any cyclic moiety is substituted with    at least one substituent selected from the group consisting of halo,    alkyl, alkylhalo, alkoxy, oxo, COR, CO₂R, SO₂R and CN;-   R is selected from the group consisting of H and alkyl;-   and-   n is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and    8;-   or a pharmaceutically acceptable salt hydrate, solvate, optical    isomer, or combination thereof;-   with the proviso that the compound is not selected from the group    consisting of:-   5-(4-Benzyl-piperazine-1-carbonyl)-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one,-   7-Methyl-5-(4-pyridin-4-ylmethyl-piperazine-1-carbonyl)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one,-   7-Methyl-5-[4-(2-pyridin-4-yl-ethyl)piperazine-1-carbonyl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one,-   4-{4-[7-Methyl-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindol-5-ylmethyl]-piperidin-1-ylmethyl}-benzonitrile,-   2-Benzyl-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile,-   7-Chloro-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carbonitrile,-   7-Methyl-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carbonitrile,-   7-Methyl-1-oxo-2-(4-chloro-benzyl)-2,3-dihydro-1H-isoindole-5-carbonitrile,-   1-Oxo-2-(4-trifluoromethoxy-benzyl)-7-trifluoromethyl-2,3-dihydro-1H-isoindole-5-carbonitrile,-   3-Oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-4,6-dicarbonitrile,-   7-Iodo-5-methoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one,-   2-Benzyl-5-methoxy-2,3-dihydro-isoindol-1-one, and-   7-Chloro-5-methoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one.

It will be understood by those of skill in the art that when compoundsof the present invention contain one or more chiral centers, thecompounds of the invention may exist in, and be isolated as,enantiomeric or diastereomeric forms, or as a racemic mixture. Thepresent invention includes any possible enantiomers, diastereomers,racemates or mixtures thereof, of a compound of formula I. The opticallyactive forms of the compound of the invention may be prepared, forexample, by chiral chromatographic separation of a racemate, bysynthesis from optically active starting materials or by asymmetricsynthesis based on the procedures described thereafter.

It will also be appreciated by those of skill in the art that certaincompounds of the present invention may exist as geometrical isomers, forexample E and Z isomers of alkenes. The present invention includes anygeometrical isomer of a compound of formula I. It will further beunderstood that the present invention encompasses tautomers of thecompounds of formula I.

It will also be understood by those of skill in the art that certaincompounds of the present invention may exist in solvated, for examplehydrated, as well as unsolvated forms. It will further be understoodthat the present invention encompasses all such solvated forms of thecompounds of formula I.

Within the scope of the invention are also salts of the compounds offormula I. Generally, pharmaceutically acceptable salts of compounds ofthe present invention are obtained using standard procedures well knownin the art, for example, by reacting a sufficiently basic compound, forexample an alkyl amine with a suitable acid, for example, HCl or aceticacid, to afford a physiologically acceptable anion. It is also possibleto make a corresponding alkali metal (such as sodium, potassium, orlithium) or an alkaline earth metal (such as a calcium) salt by treatinga compound of the present invention having a suitably acidic proton,such as a carboxylic acid or a phenol with one equivalent of an alkalimetal or alkaline earth metal hydroxide or alkoxide (such as theethoxide or methoxide), or a suitably basic organic amine (such ascholine or meglumine) in an aqueous medium, followed by conventionalpurification techniques.

In one embodiment of the present invention, the compound of formula Imay be converted to a pharmaceutically acceptable salt or solvatethereof, particularly, an acid addition salt such as a hydrochloride,hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate,methanesulphonate or p-toluenesulphonate.

In a particular embodiment of the invention, R⁵ is selected from thegroup consisting of heterocycloalkyl and C₁₋₆alkylheterocycloalkyl.

In a particular embodiment of the invention, B is selected from thegroup consisting of C₀₋₆alkylaryl, C₁₋₆alkylheteroaryl andC₀₋₆alkylheterocycloalkyl.

Specific examples of the present invention include the compounds shownin the following table, their pharmaceutically acceptable salts,hydrates, solvates, optical isomers, and combinations thereof:

Example No. Structure Name 5

7-Chloro-2-[(4,4-difluoro- cyclohexyl) methyl]-1- oxoisoindoline-5-carbonitrile 8.1

7-Chloro-5-[5-(4-hydroxy- piperidin-1-yl methyl)- [1,2,4]oxadiazol-3-yl]-2- (4-trifluoromethoxy- benzyl)-2,3-dihydro-isoindol-1-one 8.2

7-Chloro-5-[5-(4-oxo- piperidin-1-yl methyl)- [1,2,4]oxadiazol-3-yl]-2-(4-trifluoromethoxy- benzyl)-2,3-dihydro- isoindol-1-one 8.3

7-Chloro-5-[5-(4-fluoro- piperidin-1-yl methyl)- [1,2,4]oxadiazol-3-yl]-2- (4-trifluoromethoxy- benzyl)-2,3-dihydro-isoindol-1-one 8.4

7-Chloro-2-(4,4-difluoro- cyclohexyl-methyl)-5-[5-(4-fluoro-piperidin-1- ylmethyl)- [1,2,4]oxadiazol-3-yl]-2,3-dihydro-isoindol-1-one 10.4

4-{5-[7-Methyl-1-oxo-2- (4-trifluoro-methoxy- benzyl)-2,3-dihydro-1H-isoindol-5-yl]- [1,2,4]oxadiazol-3- ylmethyl}-piperazine-1- carbaldehyde11

2-Cyclopropylmethyl-5- [1-(2-fluoro-benzyl)- piperidin-4-ylmethyl]-7-methyl-2,3-dihydro- isoindol-1-one 12.2

7-Methyl-5-[3-(4-methyl- piperazin-1-ylmethyl)- [1,2,4]oxadiazol-5-yl]-2- (4-trifluoromethoxy- benzyl)-2,3-dihydro-isoindol-3-one 12.3

4-{5-[7-Methyl-1-oxo-2- (4-trifluoro-methoxy- benzyl)-2,3-dihydro-1H-isoindol-5-yl]- [1,2,4]oxadiazol-3-yl methyl}-piperazine-1- carboxylicacid tert-butyl ester 13.1

2-Cyclopropylmethyl-5- [1-(3-fluoro-benzyl)- piperidin-4-yl methyl]-7-methyl-2,3-dihydro- isoindol-1-one 13.2

2-Cyclopropylmethyl-5- [1-(2-methoxy-benzyl)- piperidin-4-yl methyl]-7-methyl-2,3-dihydro- isoindol-1-one 13.3

2-Cyclopropylmethyl-5- [1-(3-methoxy-benzyl)- piperidin-4-yl methyl]-7-methyl-2,3-dihydro- isoindol-3-one 13.4

2-Cyclopropylmethyl-5- [1-(4-methoxy-benzyl)- piperidin-4-yl methyl]-7-methyl-2,3-dihydro- isoindol-1-one 13.5

2-Cyclopropylmethyl-5- [1-(4-fluoro-benzyl)- piperidin-4-ylmethyl]-7-methyl-2,3-dihydro- isoindol-1-one 13.6

2-Cyclohexylmethyl-5-[1- (3-fluoro-benzyl)- piperidin-4-ylmethyl]-7-methyl-2,3-dihydro- isoindol-1-one 13.7

2-Cyclohexylmethyl-5-[1- (4-fluoro-benzyl)- piperidin-4-ylmethyl]-7-methyl-2,3-dihydro- isoindol-1-one 13.8

2-Cyclopropylmethyl-5- [1-(3-fluoro-benzyl)- piperidin-4-ylmethoxy]-7-methyl-2,3-dihydro- isoindol-1-one 13.9

2-Cyclopropylmethyl-5- [1-(4-methoxybenzyl)- piperidin-4-ylmethoxy]-7-methyl-2,3-dihydro- isoindol-1-one 15

5-(1-Benzyl-pyrrolidin-3- ylamino)-7-methyl-2-(4-trifluoromethoxy-benzyl)- 2,3-dihydro-isoindol-1-one 16.1

7-Methyl-5-[5-(4-methyl- piperazin-1-yl methyl)- pyridin-3-yl]2-(4-trifluoro methoxy-benzyl)-2,3- dihydro-isoindol-1-one 16.2

7-Methyl-5-[6-(4-methyl- piperazin-1-ylmethyl)-pyridin-3-yl]-2-(4-trifluoro methoxy-benzyl)-2,3- dihydro-isoindol-1-one17.1

4-{4-[7-Chloro-1-oxo-2- (4-trifluoro methoxy- benzyl)-2,3-dihydro-1H-isoindol-5-ylmethyl]- piperidin-1-ylmethyl}- benzonitrile 17.2

4-[4-(7-Chloro-2- cyclopropylmethyl-1-oxo- 2,3-dihydro-1H-isoindol- 5-ylmethyl)-piperidine-1- ylmethyl]-benzonitrile 17.3

4-{4-[7-Chloro-2-(4- chloro-benzyl)-1-oxo-2,3- dihydro-1H-isoindol-5-ylmethyl]-piperidin-1- ylmethyl}-benzonitrile 17.4

4-{4-[7-Chloro-2-(4- difluoromethoxy-benzyl)- 1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]- piperidin-1-ylmethyl}- benzonitrile 17.5

4-{4-[7-Chloro-2-(4-ethyl- benzyl)-1-oxo-2,3- dihydro-1H-isoindol-5-ylmethyl]-piperidin-1- ylmethyl}-benzonitrile 18.1

4-{4-[7-Chloro-1-oxo-2- (4-trifluoro methoxy- benzyl)-2,3-dihydro-1H-isoindol-5-ylmethyl]- piperazin-1-methyl}- nicotinonitrile 18.2

3-{3-[1-(7-Chloro-2- cyclopropylmethyl-1-oxo- 2,3-dihydro-1H-isoindol-5-yl methyl)-piperidin-4- yl]-propyl}-benzonitrile 19

7-Chloro-2- cyclopropylmethyl-1-oxo- 2,3-dihydro-1H-isoindole-5-carbonitrile 20

5-Fluoro-2-(4-ethyl- benzyl)-7-trifluoro methyl-2,3-dihydro-isoindol-1-one 21

5,7-Dimethoxy-2-(4- trifluoromethoxy-benzyl)- 2,3-dihydro-isoindol-1-one22

5,7-Dimethoxy-2-(4- chloro-benzyl)-2,3- dihydro-isoindol-1-one 23

5,7-Dimethoxy-2-[1-(4- chloro-phenyl)-ethyl]-2,3- dihydro-isoindol-1-onePharmaceutical Compositions

The compounds of the present invention may be formulated intoconventional pharmaceutical composition comprising a compound of formulaI, or a pharmaceutically acceptable salt or solvate thereof, inassociation with a pharmaceutically acceptable carrier or excipient. Thepharmaceutically acceptable carriers can be either solid or liquid.Solid form preparations include, but are not limited to, powders,tablets, dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances, which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, or table disintegrating agents. A solid carrier can also be anencapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided compound of the invention, or the activecomponent. In tablets, the active component is mixed with the carrierhaving the necessary binding properties in suitable proportions andcompacted in the shape and size desired.

For preparing suppository compositions, a low-melting wax such as amixture of fatty acid glycerides and cocoa butter is first melted andthe active ingredient is dispersed therein by, for example, stirring.The molten homogeneous mixture is then poured into convenient sizedmoulds and allowed to cool and solidify.

Suitable carriers include, but are not limited to, magnesium carbonate,magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch,tragacanth, methyl cellulose, sodium carboxymethyl cellulose,low-melting wax, cocoa butter, and the like.

The term composition is also intended to include the formulation of theactive component with encapsulating material as a carrier providing acapsule in which the active component (with or without other carriers)is surrounded by a carrier which is thus in association with it.Similarly, cachets are included.

Tablets, powders, cachets, and capsules can be used as solid dosageforms suitable for oral administration.

Liquid form compositions include solutions, suspensions, and emulsions.For example, sterile water or water propylene glycol solutions of theactive compounds may be liquid preparations suitable for parenteraladministration. Liquid compositions can also be formulated in solutionin aqueous polyethylene glycol solution.

Aqueous solutions for oral administration can be prepared by dissolvingthe active component in water and adding suitable colorants, flavoringagents, stabilizers, and thickening agents as desired. Aqueoussuspensions for oral use can be made by dispersing the finely dividedactive component in water together with a viscous material such asnatural synthetic gums, resins, methyl cellulose, sodium carboxymethylcellulose, and other suspending agents known to the pharmaceuticalformulation art. Exemplary compositions intended for oral use maycontain one or more coloring, sweetening, flavoring and/or preservativeagents.

Depending on the mode of administration, the pharmaceutical compositionwill include from about 0.05% w (percent by weight) to about 99% w, moreparticularly, from about 0.10% w to 50% w, of the compound of theinvention, all percentages by weight being based on the total weight ofthe composition.

A therapeutically effective amount for the practice of the presentinvention can be determined by one of ordinary skill in the art usingknown criteria including the age, weight and response of the individualpatient, and interpreted within the context of the disease which isbeing treated or which is being prevented.

Medical Use

We have discovered that the compounds of the present invention exhibitactivity as pharmaceuticals, in particular as modulators of metabotropicglutamate receptors. More particularly, the compounds of the presentinvention exhibit activity as potentiators of the mGluR2 receptor, andare useful in therapy, in particular for the treatment of neurologicaland psychiatric disorders associated with glutamate dysfunction in ananimal.

More specifically, the neurological and psychiatric disorders include,but are not limited to, disorders such as cerebral deficit subsequent tocardiac bypass surgery and grafting, stroke, cerebral ischemia, spinalcord trauma, head trauma, perinatal hypoxia, cardiac arrest,hypoglycemic neuronal damage, dementia (including AIDS-induceddementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateralsclerosis, ocular damage, retinopathy, cognitive disorders, idiopathicand drug-induced Parkinson's disease, muscular spasms and disordersassociated with muscular spasticity including tremors, epilepsy,convulsions, cerebral deficits secondary to prolonged statusepilepticus, migraine (including migraine headache), urinaryincontinence, substance tolerance, substance withdrawal (including,substances such as opiates, nicotine, tobacco products, alcohol,benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis,schizophrenia, anxiety (including generalized anxiety disorder, panicdisorder, social phobia, obsessive compulsive disorder, andpost-traumatic stress disorder (PTSD)), mood disorders (includingdepression, mania, bipolar disorders), circadian rhythm disorders(including jet lag and shift work), trigeminal neuralgia, hearing loss,tinnitus, macular degeneration of the eye, emesis, brain edema, pain(including acute and chronic pain states, severe pain, intractable pain,neuropathic pain, inflammatory pain, and post-traumatic pain), tardivedyskinesia, sleep disorders (including narcolepsy), attentiondeficit/hyperactivity disorder, and conduct disorder.

The invention thus provides a use of any of the compounds according toformula I, or a pharmaceutically acceptable salt or solvate thereof, forthe manufacture of a medicament for the treatment of any of theconditions discussed above.

Additionally, the invention provides a method for the treatment of asubject suffering from any of the conditions discussed above, whereby aneffective amount of a compound according to formula I or apharmaceutically acceptable salt or solvate thereof, is administered toa patient in need of such treatment. The invention also provides acompound of formula I or pharmaceutically acceptable salt or solvatethereof, as hereinbefore defined for use in therapy.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The term “therapeutic” and “therapeutically” should beconstrued accordingly. The term “therapy” within the context of thepresent invention further encompasses the administration of an effectiveamount of a compound of the present invention, to mitigate either apre-existing disease state, acute or chronic, or to mitigate a recurringcondition. This definition also encompasses prophylactic therapies forprevention of recurring conditions and continued therapy for chronicdisorders.

In use for therapy in a warm-blooded animal such as a human, thecompounds of the present invention may be administered in the form of aconventional pharmaceutical composition by any route including orally,intramuscularly, subcutaneously, topically, intranasally,intraperitoneally, intrathoracially, intravenously, epidurally,intrathecally, intracerebroventricularly and by injection into thejoints. In preferred embodiments of the invention, the route ofadministration is oral, intravenous, or intramuscular.

The dosage will depend on the route of administration, the severity ofthe disease, age and weight of the patient and other factors normallyconsidered by the attending physician, who determines the individualregimen and dosage level for a particular patient.

As mentioned above, the compounds described herein may be provided ordelivered in a form suitable for oral use, for example, in a tablet,lozenge, hard and soft capsule, aqueous solution, oily solution,emulsion, and suspension. Alternatively, the compounds may be formulatedinto a topical administration, for example, as a cream, ointment, gel,spray, or aqueous solution, oily solution, emulsion or suspension. Thecompounds described herein also may be provided in a form that issuitable for nasal administration, for example, as a nasal spray, nasaldrops, or dry powder. The compounds can be administered to the vagina orrectum in the form of a suppository. The compounds described herein alsomay be administered parentally, for example, by intravenous,intravesicular, subcutaneous, or intramuscular injection or infusion.The compounds can be administered by insufflation (for example as afinely divided powder). The compounds may also be administeredtransdermally or sublingually.

In addition to their use in therapeutic medicine, the compounds offormula I, or salts thereof, are useful as pharmacological tools in thedevelopment and standardisation of in vitro and in vivo test systems forthe evaluation of the effects of inhibitors of mGluR-related activity inlaboratory animals as part of the search for new therapeutics agents.Such animals include, for example, cats, dogs, rabbits, monkeys, ratsand mice.

Process for Preparing

Compounds of the present invention can be prepared by various syntheticprocesses. The selection of a particular process to prepare a givencompound is within the purview of the person of skill in the art. Thechoice of particular structural features and/or substituents maytherefore influence the selection of one process over another.

Within these general guidelines, the following processes can be used toprepare exemplary subsets of compounds of this invention. Unlessindicated otherwise, the variables described in the following schemesand processes have the same definitions as those given for formula Iabove.

In one process, for example, a compound of formula Ia:

is cyclized in the presence of an amine of the formula R¹(CR⁸CR⁹)_(n)NH₂to give a compound of formula Ib:

A compound of formula Ib is then cross-coupled with a suitable reagentcontaining R⁵ to yield a a compound according to formula Ic:

In one embodiment of this process, 5-substituted-7-methyl isoindolonesare synthesized as depicted in Scheme 1 below.4-bromo-2,6-dimethylaniline is converted to the corresponding nitrileunder Sandmeyer reaction conditions. The nitrile is then hydrolyzed tothe acid in a stepwise fashion. The amide can be obtained by basichydrolysis. The amide is then diazotized and hydrolyzed withnitrososulphuric acid to provide the benzoic acid, which is subsequentlyprotected as the methyl ester using standard conditions. The benzylicmethyl group is monobrominated with N-bromosuccinimide using benzoylperoxide as the radical initiator. This resultant intermediate iscyclized to the isoindolone with the appropriate amine in the presenceof a base such as potassium carbonate. Finally, substituent R⁵ wasintroduced at C5 of the isoindolone using typical Buchwald, Suzuki orStille cross-coupling reaction conditions and reagents.

In another embodiment of this process, 5-substituted-7-chloroisoindolones are synthesized as depicted in Scheme 2 below.4-bromo-2-methylbenzoic acid is chlorinated ortho to the acid usingN-chlorosuccinimide and a palladium catalyst. In the manner analogous tothat described above (Scheme 1), this acid was then esterified,brominated, and cyclized to yield the isoindolone intermediate.Substituent R⁵ is introduced similarly.

In yet another embodiment of this process, isoindolones that aresubstituted with an amide at C5 can be prepared as depicted in Scheme 3below. Thus, an appropriately substituted 5-bromoisoindolone isconverted to the corresponding nitrile using zinc cyanide in thepresence of a palladium catalyst. The nitrile is then hydrolyzed underbasic conditions to provide the benzoic acid, which was then coupledwith various amines using methodologies that are well-known in the artto provide the final compounds.

In still another embodiment, the process as described above can beadapted for the preparation of amino-propargyl and amino-alkylisoindolones. Thus, suitable 5-bromoisoindolones are first subjected toSonogashira coupling conditions with various propargyl amines as shownin Scheme 4. The resulting alkyne then can be hydrogenated using routinemethodologies to provide the amino-alkyl substituted product. In Scheme4, R and R′ correspond to substituents as defined herein for R¹⁰ andR¹¹.

Another process according to this invention adapts some of the foregoingsynthetic methodology for the preparation of compounds bearingN-propargylic substituents. Thus, a compound of the formula Ia:

is cyclized in the presence of propargyl amine into a compound of theformula Id:

Coupling a compound of formula Id with a reagent comprising R¹ gives acompound of formula Ie:

R¹ preferably is an aryl group. A compound of formula Ie is thencross-coupled with a reagent comprising R⁵, thereby yielding a compoundaccording to formula If:

One embodiment of this process is shown in Scheme 5 below. The terminalalkyne is coupled with various aryl groups using standard Sonogashiracoupling conditions. Finally, substituent R⁵ was introduced at C5 usingtypical Buchwald, Suzuki or Stille cross-coupling reaction conditions asindicated in Scheme 5.

Another process of the invention contemplates the preparation ofcompounds of formula I that are unsubstituted on the isoindolonearomatic ring. This subset of compounds are be straightforwardlyprepared as depicted below in Scheme 6. Thus, phthalimide is reduced,for example with tin under acidic conditions, to provide isoindolinone.This intermediate is alkylated with various electrophiles under basicconditions to provide the desired final products. In Scheme 6, X can beany suitable leaving group such as, for example, halo, such as bromo andiodo; and tosylate.

Many variations of the foregoing processes and additions thereto appearthroughout the examples that follow. The person of ordinary skill in theart thus will appreciate that the compounds of this invention can beprepared by following or adapting one or more of the processes disclosedherein.

The invention is further illustrated by way of the following examples,which are intended to elaborate several embodiments of the invention.These examples are not intended to, nor are they to be construed to,limit the scope of the invention. It will be clear that the inventionmay be practiced otherwise than as particularly described herein.Numerous modifications and variations of the present invention arepossible in view of the teachings herein and, therefore, are within thescope of the invention.

General Methods

All starting materials are commercially available or earlier describedin the literature.

The ¹H and ¹³C NMR spectra were recorded either on Bruker 300, BrukerDPX400 or Varian +400 spectrometers operating at 300, 400 and 400 MHzfor ¹H NMR respectively, using TMS or the residual solvent signal asreference, in deuterated chloroform as solvent unless otherwiseindicated. All reported chemical shifts are in ppm on the delta-scale,and the fine splitting of the signals as appearing in the recordings (s:singlet, br s: broad singlet, d: doublet, t: triplet, q: quartet, m:multiplet).

Analytical in line liquid chromatography separations followed by massspectra detections, were recorded on a Waters LCMS consisting of anAlliance 2795 (LC) and a ZQ single quadropole mass spectrometer. Themass spectrometer was equipped with an electrospray ion source operatedin a positive and/or negative ion mode. The ion spray voltage was ±3 kVand the mass spectrometer was scanned from m/z 100-700 at a scan time of0.8 s. To the column, X-Terra MS, Waters, C8, 2.1×50 mm, 3.5 mm, wasapplied a linear gradient from 5% to 100% acetonitrile in 10 mM ammoniumacetate (aq.), or in 0.1% TFA (aq.).

Preparative reversed phase chromatography was run on a Gilsonautopreparative HPLC with a diode array detector using an XTerra MS C8,19×300 mm, 7 mm as column.

Purification by a chromatotron was performed on rotating silicagel/gypsum (Merck, 60 PF-254 with calcium sulphate) coated glass sheets,with coating layer of 1, 2, or 4 mm using a TC Research 7924Tchromatotron.

Purification of products were also done using Chem Elut ExtractionColumns (Varian, cat #1219-8002), Mega BE-SI (Bond Elut Silica) SPEColumns (Varian, cat #12256018; 12256026; 12256034), or by flashchromatography in silica-filled glass columns.

Microwave heating was performed in a Smith Synthesizer Single-modemicrowave cavity producing continuous irradiation at 2450 MHz (PersonalChemistry AB, Uppsala, Sweden).

The pharmacological properties of the compounds of the invention can beanalyzed using standard assays for functional activity. Examples ofglutamate receptor assays are well known in the art as described in, forexample, Aramori et al., 1992, Neuron, 8:757; Tanabe et al., 1992,Neuron, 8:169; Miller et al., 1995, J. Neuroscience, 15:6103; Balazs, etal., 1997, J. Neurochemistry, 1997, 69:151. The methodology described inthese publications is incorporated herein by reference. Conveniently,the compounds of the invention can be studied by means of an assay thatmeasures the mobilization of intracellular calcium, [Ca²⁺]_(i) in cellsexpressing mGluR2.

Fluorometric Imaging Plate Reader (FLIPR) analysis was used to detectallosteric activators of mGluR2 via calcium mobilization. A clonal HEK293 cell line expressing a chimeric mGluR2/CaR construct comprising theextracellular and transmembrane domains of human mGluR2 and theintracellular domain of the human calcium receptor, fused to thepromiscuous chimeric protein G_(αqi5) was used. Activation of thisconstruct by agonists or allosteric activators resulted in stimulationof the PLC pathway and the subsequent mobilization of intracellular Ca²⁺which was measured via FLIPR analysis. At 24-hours prior to analysis,the cells were trypsinized and plated in DMEM at 100,000 cells/well inblack sided, clear-bottom, collagen I coated, 96-well plates. The plateswere incubated under 5% CO₂ at 37° C. overnight. Cells were loaded with6 μM fluo-3 acetoxymethylester (Molecular Probes, Eugene Oreg.) for 60minutes at room temperature. All assays were performed in a buffercontaining 126 mM NaCl, 5 mM KCl, 1 mM MgCl₂, 1 mM CaCl₂, 20 mM Hepes,0.06M DCG-IV (a Group II mGluR selective agonist), supplemented with 1.0mg/ml D-glucose and 1.0 mg/ml BSA fraction IV (pH 7.4).

FLIPR experiments were done using a laser setting of 0.8 W and a 0.4second CCD camera shutter speed. Extracellular fluo-3 was washed off andcells were maintained in 160 μL of buffer and placed in the FLIPR. Anaddition of test compound (0.01 μM to 30 μM in duplicate) was made after10 seconds of baseline fluorescent readings were recorded on FLIPR.Fluorescent signals were then recorded for an additional 75 seconds atwhich point a second addition of DCG-IV (0.2 μM) was made andfluorescent signals were recorded for an additional 65 seconds.Fluorescent signals were measured as the peak height of the responsewithin the sample period. Data was analyzed using Assay Explorer, andEC₅₀ and E_(max) values (relative to maximum DCG-IV effect) werecalculated using a four parameter logistic equation.

A [³⁵S]-GTPγS binding assay was used to functionally assay mGluR2receptor activation. The allosteric activator activity of compounds atthe human mGluR2 receptor were measured using a [³⁵S]-GTPγS bindingassay with membranes prepared from CHO cells which stably express thehuman mGluR2. The assay is based upon the principle that agonists bindto G-protein coupled receptors to stimulate GDP-GTP exchange at theG-protein. Since [³⁵S]-GTPγS is a non-hydrolyzable GTP analog, it can beused to provide an index of GDP-GTP exchange and, thus, receptoractivation. The GTPγS binding assay therefore provides a quantitativemeasure of receptor activation.

Membranes were prepared from CHO cells stably transfected with humanmGluR2. Membranes (30 μg protein) were incubated with test compound (3nM to 300 μM) for 15 minutes at room temperature prior to the additionof 1 μm glutamate, and incubated for 30 min at 30° C. in 500 μl assaybuffer (20 mM HEPES, 100 mM NaCl, 10 mM MgCl₂), containing 30 μM GDP and0.1 nM [³⁵S]-GTPγS (1250 Ci/mmol). Reactions were carried out intriplicate in 2 ml polypropylene 96-well plates. Reactions wereterminated by vacuum filtration using a Packard 96-well harvester andUnifilter-96, GF/B filter microplates. The filter plates were washed4×1.5 ml with ice-cold wash buffer (10 mM sodium phosphate buffer, pH7.4). The filter plates were dried and 35 μl of scintillation fluid(Microscint 20) was added to each well. The amount of radioactivitybound was determined by counting plates on the Packard TopCount. Datawas analyzed using GraphPad Prism, and EC₅₀ and E_(max) values (relativeto the maximum glutamate effect) were calculated using non-linearregression.

Generally, the compounds of the present invention were active in assaysdescribed herein at concentrations (or with EC₅₀ values) less than 10μM. For example, compounds of Examples 8.3, 10.4, 11 and 13.7 and haveEC50 values 75, 230, 84 and 28 nM, respectively.

Example 1 4,4-Difluorocyclohexanecarboxamide

A suspension of ethyl 4,4-difluorocyclohexanecarboxylate (2500 mg, 13mmol) in ammonium hydroxide (28%, 50 ml) was stirred at 60° C.overnight. After removal of solvent, the residue was washed with water.The precipitate was obtained as product (white solid, 800 mg). ¹H NMR(300 MHz, CDCl₃): δ 5.31-5.45 (br, 2H), 2.02-2.27 (m, 3H), 1.92-2.02 (m,2H), 1.72-1.87 (m, 4H). The mother liquor was acidified with 1N HCl topH<1. The compound was extracted with EtOAc. The organic layer waswashed with water, brine, dried over anhydrous sodium sulphate,filtered, condensed. 4,4-difluorocyclohexanecarboxylic acid was obtainedas a 1200 mg of white solid which was further converted to4,4-difluorocyclohexanecarboxamide by following procedure.

To a solution of 4,4-difluorocyclohexanecarboxylic acid (1.35 g, 8.22mmol) in THF (50 ml), 4-methylmorpholine (831 mg, 8.22 mmol)was added at−70° C. followed by isobutyl chloridocarbonate (1140 mg, 8.22 mmol). 10mins later, ammonium hydroxide (28%, 10 ml) was added. The resultingmixture was allowed to warm up to 0° C. After removal of all solvents,the residue was washed with water, hexanes to provide a 1.06 g of whitesolid which was 4,4-difluorocyclohexanecarboxamide. Total yield was 82%.

Example 2 [(4,4-Difluorocyclohexyl)methyl]amine

4,4-difluorocyclohexanecarboxamide (1.32 g, 8.10 mmol) was stirred inthe solution of lithium borohydrate (1M, 30 ml) under nitrogenovernight. Then, the reaction mixture was refluxed for 4 hours. Aftercooled to room temperature, it was poured into ice-water slowly. Afterfiltration, the product was extracted with dichloromethane fromfiltrate. Combined organic layers were water, brine, dried overanhydrous sodium sulphate, filtered and condensed to provide a 934 mg ofcolorless oil (82%). δ 2.53 (d, 2H), 1.98-2.09 (m, 2H), 1.73-1.82 (m,6H), 1.17-1.29 (m, 3H).

Example 3 Tert-butyl 4-fluorocyclohexanecarboxylate

To a solution of tert-butyl 4-hydroxycyclohexanecarboxylate (1500 mg,7.45 mmol) in dichloromethane (anhydrous, 20 ml), DAST was (1571 mg,22.4 mmol) added at 0° C. The resulting mixture was stirred at 0° C. for3 hours. The mixture was diluted with dichloromethane, quenched withsodium bicarbonate. The organic layer was separated, the aqueous phasewas extracted with EtOAc. The combined organic layer were washed withwater, brine, dried with androus sodium sulphate. The product waspurified (flash chromatography, 10 to 20% EtOAc/hexanes) and obtained asa 210 mg of yellow oil (25%). ¹H NMR (300 MHz, CDCl₃): δ 5.60-5.80 (m,1H), 4.99-5.09 (m, 2H), 4.73 (d, 2H), 3.34 (br, 2H), 2.29-2.32 (m, 2H),1.44-1.46 (m, 9H).

Example 45-Bromo-7-chloro-2-[(4,4-difluorocyclohexyl)methyl]isoindolin-1-one

4-Bromo-2-bromomethyl-6-chlorobenzoic acid methyl ester (3.5 g, 9.35mmol), (4,4-difluorocyclohexyl)methylamine (1.7 g, 11.39 mmol) and K₂CO₃(3.15 g, 22.78 mmol) were stirred in toluene (10 mL) at 95° C. for 12hours. The reaction was partitioned between ethyl acetate and water andthe organic layer was washed with brine and dried over anhydrousNa₂—SO₄. The solvent was removed under reduced pressure and the productwas purified by column chromatography (10-25% EtOAc/Hexanes) to affordthe title compound as a yellow foam (2.2 g, 45%), ¹H NMR (300 MHz,CDCl₃): 7.58 (s, 1H), 7.50 (s, 1H), 4.36 (s, 2H), 3.48 (d, 2H),2.10-2.14 (m, 2H), 1.64-1.82 (m, 5H), 1.35-1.447 (m, 2H)

Example 57-Chloro-2-[(4,4-difluorocyclohexyl)methyl]-1-oxoisoindoline-5-carbonitrile

5-bromo-7-chloro-2-[(4,4-difluorocyclohexyl)methyl]isoindolin-1-one(1.14 g, 3.01 mmol) was set stirring in DMF (10 mL) under argon andZn(CN)₂ (389 mg, 3.31 mmol) and Pd(PPh₃)₄ (347 mg, 0.3 mmol) were added.The reaction was stirred at 80° C. for 1.5 hours. The reaction waspartitioned between ethyl acetate and water and the organic layer waswashed with brine and dried over anhydrous Na₂SO₄. The solvent wasremoved under reduced pressure and the product was purified by columnchromatography (40% EtOAc/Hexanes) to afford the title compound as ayellow foam (60 mg, 80%). ¹H NMR (300 MHz, CDCl₃): 7.72 (s, 1H), 7.65(s, 1H), 4.45 (s, 2H), 3.53 (d, 2H), 2.11-2.15 (m, 2H), 1.66-1.91 (m,5H), 1.41-1.50 (m, 2H)

Example 67-Chloro-5-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]-2-[(4,4-difluoro-cyclohexyl)methyl]isoindolin-1-one

To a solution of7-Chloro-N-hydroxy-1-oxo-2-[(4,4-difluorocyclohexyl)methyl]-2,3-dihydro-1H-isoindole-5-carboxamidine(450 mg, 1.26 mmol) in acetonitrile (10 ml), chloroacetyl chloride (170mg, 1.51 mmol) was added, followed by K₂CO₃ (260 mg, 1.89 mmol). Themixture was stirred overnight. After diluter with EtOAc (20 ml), it waswashed with water, brine, dried over anhydrous sodium sulphate, filteredand concentrated to provide a yellow foam. This foam was stirred in DMF(2 ml) at 140° C. for 3 hours. After cooled to room temperature, it wasdiluted with water (5 ml). The product was extracted with EtOAc. Theorganic layer was washed with water, brine, dried over anhydrous sodiumsulphate, filtered and concentrated. The product was purified by columnchromatography (40 to 60% EtOAc in hexanes) to yield the title compoundas a white solid

Example 7.17-Chloro-N-hydroxy-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carboxamidine

To a suspension of7-chloro-1-oxo-2-[4-(trifluoromethoxy)benzyl]isoindoline-5-carbonitrile(500 mg, 1.36 mmol) in ethanol (2 ml), 8-hydroxyquinoline (495 mg, 3.41mmol) was added, followed by a solution of hydroxylamine hydrochloride(199 mg, 2.86 mmol) in water (1 ml) and a solution of sodium carbonate(230 mg, 2.2 mmol) in water (1 ml). The resulting mixture was refluxedfor 4 hours. After removal of solvents, the residue was loaded to aflash chromatography. The product was purified (20% EtOAc/hexanes to 2%ammonia in MeOH/EtOAc) and obtained a 500 mg of greenish foam (90%). ¹HNMR (300 MHz, CDCl₃): δ 10.04 (s, 1H) 7.48-7.61 (m, 2H), 7.28-7.36 (m,2H), 7.17-7.21 (m, 2H), 6.04 (br, 1H), 4.77 (s, 2H), 4.22 (s, 2H).

The following compounds were made in a similar manner:

Example Structure Name Yield 7.2

7-Chloro-2-(4-chlorobenzyl)-N′- hydroxy-1-oxoisoindoline-5-carboximidamide 930 mg, (85%), brown solid NMR 10.04 (s, 1H), 7.76-7.80(m, 2H), 7.29-7.43 (m, 4H), 6.02 (s, 2H), 4.70 (s, 2H), 4.38 (s, 2H).7.3

7-Chloro-2-(cyclopropylmethyl)- N′-hydroxy-11-oxoisoindoline-5-carboximidamide 700 mg, (80%), brown solid NMR 10.01 (s, 1H), 7.77-7.83(m, 2H), 5.90 (s, 2H), 4.54 (s, 2H), 3.40 (d, 2H), 0.99-1.06 (m, 1H),0.53-0.58 (m, 2H), 0.33-0.39 (m, 2H). 7.4

7-Chloro-2-[(4,4- difluorocyclohexyl)methyl]-N′-hydroxy-1-oxoisoindoline-5- carboximidamide 800 mg, (87%), yellow solidNMR 10.01 (s, 1H), 7.59-4.63 (m, 2H), 4.92 (s, 2H), 4.42 (s, 2H), 3.51(d, 2H), 2.10-2.15 (m, 1H), 1.61-1.81 (m, 6H), 1.40-1.45 (m, 2H).

Example 8.17-Chloro-5-[5-(4-hydroxy-piperidin-1-ylmethyl)-[1,2,4]oxadiazol-3-yl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one

To a mixture of 4-Hydroxy piperidine (9.9 mg, 0.098 mmol),7-chloro-5-chloromethyl-[1,2,4]oxadiazol-3-yl)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one(30 mg, 0.065 mmol) and potassium carbonate (27 mg, 0.195 mmol) wasadded acetonitrile (3.0 mL). The mixture was allowed to stir at roomtemperature overnight. Water (2.0 mL) was added and the product wasextracted with ethyl acetate. The organic layer was washed with water,brine, dried over sodium sulfate, filtered and concentrated. Columnchromatography provided the title compound as a yellow oil, 16.7 mg(49%). ¹H NMR (300 MHz, CDCl₃): δ 8.20 (s, 1H), 8.04 (s, 1H), 7.38-7.41(m, 2H), 7.20-7.23 (m, 2H), 4.82 (s, 2H), 4.34 (s, 2H), 3.95 (s, 2H),3.75 (br, 1H), 2.90-2.93 (m, 2H), 2.42-2.50 (m, 2H), 1.94-1.99 (m, 2H),1.64-1.74 (m, 3H)

The following compounds were prepared in a similar manner:

Example Structure Name Yield 8.2

7-Chloro-5-[5-(4-oxo- piperidin-1-ylmethyl)- [1,2,4]oxadiazol-3-yl]-2-(4-trifluoromethoxy- benzyl)-2,3-dihydro- isoindol-1-one 23.8 mg (70%),yellow oil NMR 8.19 (s, 1H), 8.04 (s, 1H), 7.37-7.41 (m, 2H), 7.20-7.23(m, 2H), 4.82 (s, 2H), 4.34 (m, 2H), 4.10 (s, 2H), 3.00 (t, 2H), 2.56(t, 2H) 8.3

7-Chloro-5-[5-(4-fluoro- piperidin-1-ylmethyl)-[1,2,4]oxadiazol-3-yl]-2- (4-trifluoromethoxy- benzyl)-2,3-dihydro-isoindol-1-one 22.1 mg (50%), yellow oil NMR 8.19 (s, 1H), 8.02 (s, 1H),7.32-7.40 (m, 2H), 7.11-7.19 (m, 2H), 4.79 (s, 2H), 4.30 (s, 2H), 3.94(s, 2H), 3.75 (br, 1H), 2.85-2.95 (m, 2H), 2.40-2.50 1.85-1.95 (m, 2H),1.60- 1.75 (m, 2H) 8.4

7-Chloro-2-(4,4-difluoro- cyclohexylmethyl)-5-[5- (4-fluoro-piperidin-1-ylmethyl)-[1,2,4] oxadiazol-3-yl]-2,3- dihydro-isoindol-1-one 33.2 mg(95%), white solid NMR 8.50 (s, 1H), 8.24 (s, 1H), 4.68 (s, 2H), 3.94(s, 2H), 3.75 (br, 1H), 2.89-3,54 (m, 2H), 2.80-3.00 (m, 2H), 2.45-2.55(m, 2H), 2.05-2.2 (m, 2H), 1.85-1.95 (m, 3H), 1.35-1.85 (m, 8H)

Example 9.14-(2-Cyclopropylmethyl-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl)-piperidine-1-carboxylicacid tert-butyl ester

To a purged (Argon) sample of 4-Methylene-piperidine-1-carboxylic acidtert-butyl ester (727 mg, 3.68 mmol) was added 9-BBN (11.32 mL, 5.66mmol). The mixture was stirred at 60° C. for two hours. After cooling toroom temperature this solution was added to5-Bromo-7-methyl-2-cyclopropylmethyl-2,3-dihydro-isoindol-1-one (794 mg,2.83 mmol), Pd(dppf)Cl₂ (115 mg, 0.142 mmol), DMF (25 mL), potassiumcarbonate (1.17 g, 8.49 mmol) and water (2.5 mL). The mixture wasallowed to stir at 75° C. for 1.5 hours. The mixture was then cooled toroom temperature and poured into water (3 mL). The product was extractedwith ethyl acetate. The combined organic layers were washed with waterthree times, brine, dried over sodium sulphate, filtered andconcentrated. Column chromatography (30% Ethyl acetate/hexanes) providedthe title compound as a light yellow oil (777 mg, 53%). ¹H NMR (300 MHz,CDCl₃): δ 7.01 (s, 1H), 6.94 (s, 1H), 4.39 (s, 2H), 3.42 (d, 2H), 2.68(s, 3H), 2.57 (s, 2H), 2.54 (d, 2H), 1.70-1.62 (m, 4H), 1.43 (s, 9H),1.09 (d, 1H), 1.01 (m, 1H), 0.56-0.5 (m, 2H), 0.31-0.29 (m, 2H).

The following compound was prepared in a similar manner:

Example Structure Name Yield 9.2

4-(2-Cyclohexylmethyl-7- methyl-1-oxo-2,3- dihydro-1H-isoindol-5-ylmethyl)-piperidine-1- carboxylic acid tert-butyl ester 658 mg 48%colourless solid NMR 7.00 (s, 2H), 6.97 (s, 1H), 4.31 (s, 2H), 3.42-3.40(d, 2H), 2.71 (s, 3H), 2.65-2.57 (m, 4H), 1.73-1.61 (m, 9H), 1.47 (s,9H), 1.25-0.90 (m, 7H)

Example 10.12-Cyclopropylrethyl-7-methyl-5-piperidin-4-ylmethyl-2,3-dihydro-isoindol-1-one

4-[7-Methyl-1-oxo-2-cyclopropylmethyl-2,3-dihydro-1H-isoindol-5-yl]-piperidine-1-carboxylicacid tert-butyl ester (777 mg, 1.95 mmol) was dissolved in formic acid(10 mL) and stirred at room temperature for 0.5 hours. The formic acidwas removed under reduced pressure and the product was neutralized withNaHCO₃ and extracted with CH₂Cl₂. The organic layer was washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrate to affordthe title compound (578 mg, 99%) as a brown oil. ¹H NMR (300 MHz,CDCl₃): δ 7.02 (s, 1H), 6.95 (s, 1H), 4.40 (s, 2H), 3.43 (d, 2H),3.07-3.03 (d, 2H), 2.69 (s, 3H), 2.56-2.38 (m, 4H), 2.38 (br s, 1H),1.64-1.61 (m, 4H), 1.19-1.15 (m, 2H), 1.02 (m, 1H), 0.57-0.53 (m, 2H),0.34-0.30 (m, 2H).

The following compounds were prepared in a similar manner:

Example Structure Name Yield 10.2

2-Cyclohexylmethyl-7- methyl-5-piperidin-4- ylmethyl-2,3-dihydro-isoindol-1-one 501 mg 99% bron oil NMR 7.01 (s, 1H), 6.97 (s, 1H), 4.30(s, 2H), 3.42-3.40 (d, 2H), 3.14-3.10 (d, 2H), 2.71 (s, 3H), 2.63-2.57(m, 4H), 1.73-1.67 (m, 9H), 1.30-1.19 (m, 4H), 1.05-1.02 (m, 3H). 10.3

2-Cyclopropylmethyl-7- methyl-5-(piperidin-4- ylmethoxy)-2,3-dihydro-isoindol-1-one 294 mg 94% yellow solid NMR 6.74 (s, 1H), 6.70 (s, 1H),4.38 (s, 2H), 3.83-3.81 (d, 2H), 3.43-3.41 (d, 2H), 3.17-3.13 (d, 2H),2.71-2.64 (m, 5H), 2.37 (br s, 1H), 1.95-1.82 (m, 3H), 1.36-1.28 (m,2H), 1.02 (m, 1H), 0.57-0.53 (m, 2H), 0.33-0.29 (m, 2H). 10.4

4-{5-[7-Methyl-1-oxo-2- (4-trifluoromethoxy- benzyl)-2,3-dihydro-1H-isoindol-5-yl]-[1,2,4] oxadiazol-3-ylmethyl}- piperazine-1- carbaldehyde30 mg 52% yellow solid NMR 8.05 (s, 2H), 8.00 (s, 1H), 7.39-7.38 (d,2H), 7.23-7.20 (d, 2H), 4.82 (s, 2H), 4.34 (s, 2H), 3.84 (s, 2H),3.66-3.63 (m, 2H), 3.48-3.45 (m, 2H), 2.86 (s, 3H), 2.68-2.62 (m, 4H).

Example 112-Cyclopropylmethyl-5-[1-(2-fluorobenzyl)-piperidin-4-ylmethyl]-7-methyl-2,3-dihydro-isoindol-1-one

To a mixture of 2-Fluorobenzyl bromide (47 μL, 0.377 mmol),7-methyl-5-piperidin-4-ylmethyl-2-cyclohexylpropyl-2,3-dihydro-isoindol-1-one(75 mg, 0.251 mmol) and potassium carbonate (104 mg, 0.753 mmol) wasadded acetonitrile (3.0 mL). The mixture was stirred at 80° C. for 4hours. 1 scoop of Sodium tert-butoxide (˜200 mg) was added and stirringcontinued overnight at 80° C. The mixture was cooled to roomtemperature, water (2.0 mL) was added and the product was extracted withethyl acetate. The organic layer was washed with water, brine, driedover sodium sulfate, filtered and concentrated. Column chromatographyprovided the title compound as a yellow oil (6.6 mg, 6%). ¹H NMR (300MHz, CDCl₃): δ 7.38 (m, 1H), 7.23-7.13 (m, 1H), 7.11-7.00 (m, 3H), 6.96(s, 1H), 4.41 (s, 2H), 3.61 (s, 2H), 3.46-3.44 (d, 2H), 2.95-2.92 (d,2H), 2.70 (s, 3H), 2.59-2.57 (d, 2H), 2.01-1.98 (t, 2H), 1.65-1.61 (m,3H), 1.38-1.27 (m, 2H), 1.04 (m, 1H), 0.60-0.55 (m, 2H), 0.36-0.32 (m,2H).

Example 12.12-Cyclohexylmethyl-7-methyl-5-(1-pyrimidin-2-ylmethyl-piperidin-4-ylmethyl)-2,3-dihydro-isoindol-1-one

To a mixture of 2-Chloromethylpyrimidine (32 mg, 0.247 mmol),2-Cyclohexylmethyl-7-methyl-5-piperidin-4-ylmethyl-2,3-dihydro-isoindol-1-one(56 mg, 0.164 mmol) and cesium carbonate (160 mg, 0.492 mmol) was addedacetonitrile (3.0 mL). The mixture was allowed to stir at roomtemperature overnight. Water (2.0 mL) was added and the product wasextracted with ethyl acetate. The organic layer was washed with water,brine, dried over sodium sulfate, filtered and concentrated. Columnchromatography provided the title compound as a yellow oil (48 mg, 69%).¹H NMR (300 Adz, CDCl₃): δ 8.76-8.72 (d, 2H), 7.18 (t, 1H), 6.99 (s,1H), 6.95 (s, 1H), 4.30 (s, 2H), 3.78 (s, 2H), 3.40-3.37 (d, 2H),2.97-2.93 (d, 2H), 2.70 (s, 3H), 2.58-2.56 (d, 2H), 2.10-2.05 (t, 2H),1.71-1.42 (m, 10H), 1.26-1.13 (m, 4H), 1.09-0.98 (m, 2H).

The following compounds were prepared in a similar manner:

Example Structure Name Yield 12.2

7-Methyl-5-[3-(4-methyl- piperazin-1-ylmethyl)-[1,2,4]oxadiazol-5-yl]-2- -(4-trifluoromethoxy- benzyl)-2,3-dihydro-isoindol-1-one 50 mg 88% colourless solid NMR 8.04 (s, 1H), 7.99 (s,1H), 7.39-7.34 (c, 2H), 7.22-7.19 (d, 1H), 4.80 (s, 2H), 4.33 (s, 2H),3.79 (s, 3H), 2.78-2.68 (br s, 4H), 2.62-2.51 (br s, 4H), 2.30 (s, 3H).12.3

4-{5-[7-Methyl-1-oxo-2- (4-trifluoromthoxy- benzyl)-2,3-dihydro-1H-isoindol-5-yl]-[1,2,4] oxadiazol-3-ylmethyl}- piperazine-1-carboxylicacid tert-butyl ester 60 mg colourless solid NMR 8.05 (s, 1H), 8.00 (s,1H), 7.36-7.36 (s, 2H), 7.23-7.20 (d, 2H), 4.81 (s, 2H), 4.34 (s, 2H),3.80 (s, 2H)3.52-3.47 (m, 4H), 2.85 (s, 3H), 2.60-2.57 (m, 4H), 1.46 (s,9H).

Example 13.12-Cyclopropylmethyl-5-[1-(3-fluoro-benzyl)-piperidin-4-ylmethyl]-7-methyl-2,3-dihydro-isoindol-1-one

To a solution of2-Cyclopropylmethyl-7-methyl-5-piperidin-4-ylmethyl-2,3-dihydro-isoindol-1-one(30 mg, 0.110 mmol) in methanol (2 mL) was slowly added acetic acid (1mL). After stirring at room temperature for 5 minutes,3-Fluoro-benzaldehyde (12.8 μL, 0.121 mmol) and sodium cyanoborohydride(8 μL, 0.111 mmol) were added dropwisely. The mixture stirred at roomtemperature for 2 hours and was neutralized with saturated sodiumbicarbonate (10 mL). The aqueous mixture was extracted withdichloromethane and the organics were dried over anhydrous sodiumsulfate, filtered and concentrated. Column chromatography (10-40% ethylacetate in hexanes) provided the title compound as a yellow oil. ¹H NMR(300 MHz, CDCl₃): δ 7.70-7.23 (m, 1H), 7.09-7.03 (m, 3H), 6.97-6.92 (m,2H), 4.41 (s, 2H), 3.48-3.44 (m, 4H), 2.88-2.85 (d, 2H), 2.71 (s, 3M),2.60-2.57 (d, 2H), 1.93 (t, 2H), 1.64-1.50 (m, 3H), 1.36-1.28 (m, 2H),1.04 (m, 1H), 0.60-0.55 (m, 2H), 0.34-0.32 (m, 2H)

The following compounds were prepared in a similar manner:

Example Structure Name Yield 13.2

2-Cyclopropylmethyl-5- [1-(2-methoxybenzyl)- piperidin-4-ylmethyl]-7-methyl-2,3-dihydro- isoindol-1-one 7.3 mg 11% colourless oil NMR7.36-7.34 (d, 1H), 7.23-7.20 (m, 1H), 7.02 (s, 1H), 6.96-6.85 (m, 3H),4.41 (s, 2H), 3.81 (s, 3H), 3.55 (s, 2H), 3.46-3.43 (d, 2H), 2.95-2.91(d, 2H), 2.70 (s, 3H), 2.60-2.57 (d, 2H), 1.98 (t, 2H), 1.70 (br s, 2H),1.63-1.59 (m, 3H), 1.39-1.37 (m, 2H), 1.04 (m, 1H), 0.60-0.55 (m, 2H),0.36-0.32 (m, 2H) 13.3

2-Cyclopropylmethyl-5- [1-(3-mthoxybenzyl)- piperidin-4-ylmethyl]-7-methyl-2,3-dihydro- isoindol-1-one 40 mg 60% yellow oil NMR 7.26-7.20(m, 1H), 7.03 (s, 1H), 6.97 (s, 1H), 6.91-6.89 (m, 3H), 4.41 (s, 2H),3.82 (s, 3H), 3.47-3.44 (m, 4H), 2.90-2.86 (d, 2H), 2.71 (s, 3H),2.59-2.57 (d, 2H), 1.92 (t, 2H), 1.64-1.59 (m, 3H), 1.36-1.35 (m, 2H),1.04 (m, 1H), 0.59-0.55 (m, 2H), 0.36-0.32 (m, 2H) 13.4

2-Cyclopropylmethyl-5- [1-(4-methoxybenzyl)- piperidin-4-ylmethyl]-7-methyl-2,3-dihydro- isoindol-1-one 23 mg 34% yellow oil NMR 7.23-7.21(d, 2H), 7.02 (s, 1H), 6.96 (s, 1H), 6.87-6.84 (, 2H), 4.41 (s, 2H),3.82 (s, 3H), 3.46-3.44 (m, 4H), 2.89-2.85 (d, 2H), 2.70 (s, 3H),2.58-2.56 (d, 2H), 1.91 (t, 2H), 1.63-1.59 (m, 3H), 1.34-1.32 (m, 2H),1.04 (m, 1H), 0.59-0.55 (m, 2H), 0.36-0.32 (m, 2H) 13.5

2- Cyclopropylmethyl- 5-[1-(4- fluorobenzyl)- piperidin-4-ylmethyl]-7-methyl- 2,3-dihydro-isoindol- 1-one 36 mg 35% light yellowoil NMR 7.29-7.24 (m, 2H), 7.02-6.97 (m, 4H), 4.41 (s, 2H), 3.61 (s,2H), 3.46-3.44 (m, 4H), 2.87-2.83 (d, 2H), 2.70 (s, 3H), 2.59-2.57 (d,2H), 1.90-1.86 (t, 2H), 1.63-1.59 (m, 3H), 1.34-1.30 (m, 2H), 1.04 (m,1H), 0.60-0.55 (m, 2H), 0.35-0.32 (m, 2H) 13.6

2-Cyclohexylmethyl-5- [1-(3-fluoro-benzyl)- piperidin-4-ylmethyl]-7-methyl-2,3-ddihydro- isoindol-1-one 34 mg 43% colourless oil NMR7.30-7.23 (m, 1H), 7.09-7.04 (m, 2H), 7.00-6.92 (m, 3H), 4.29 (s, 2H),3.48 (s, 2H), 3.41-3.39 (d, 2H), 2.88-2.84 (d, 2H), 2.70 (s, 3H),2.59-2.57 (d, 2H), 1.86-1.89 (t, 2H), 1.73-1.60 (m, 8H), 1.35-1.19 (m,6H), 1.05 (m, 2H) 13.7

2-Cyclohexylmethyl-5- [1-(4-fluoro-benzyl)- piperidin-4-ylmethyl]-7-methyl-2,3-dihydro- isoindol-1-one 26 mg 33% light yellow oil NMR7.29-7.24 (m, 2H), 7.03-6.96 (m, 4H), 4.29 (s, 2H), 3.45 (s, 2H),3.41-3.39 (d, 2H), 2.87-2.83 (d, 2H), 2.70 (s, 3H), 2.58-2.56 (d, 2H),1.90-1.86 (t, 2H), 1.76-1.59 (m, 9H), 1.34-1.19 (m, 5H), 1.06 (m, 2H)13.8

2-Cyclopropyomethyl-5- [1-(3-fluorobenzyl)- piperidin-4-ylmethoxy]-7-methyl-2,3-dihydro- isoindol-1-one 27 mg 26% yellow oil NMR 7.32-7.25(m, 1H), 7.11-7.08 (m, 2H), 6.98-6.95 (m, 1H), 6.75-6.72 (d, 2H), 4.38(s, 2H), 3.86-3.84 (d, 2H), 3.52 (s, 2H), 3.44-3.42 (d, 2H), 2.96-2.92(d, 2H), 2.70 (s, 3H), 2.07-2.04 (t, 2H), 1.85-1.82 (m, 3H), 1.45 (m,2H), 1.04 (m, 1H), 0.59-0.55 (m, 2H), 0.35-0.31 (m, 2H) 13.9

2-Cyclopropylmethyl-5- [1-(4-methoxy- benzyl)-piperidin-4- ylmethoxy]-7-methyl-2,3-dihydro- isoindol-1-one 24 mg 39% yellow oil NMR 7.28-7.22(m, 1H), 7.11-7.08 (m, 2H), 6.94-6.91 (m, 2H), 6.83-6.81 (d, 1H),6.79-6.71 (d, 2H), 4.38 (s, 2H), 3.86-3.83 (m, 5H), 3.52 (s, 2H),3.44-3.42 (d, 2H), 2.98-2.94 (d, 2H), 2.70 (s, 3H), 2.06-1.99 (t, 2H),1.85-1.82 (m, 3H), 1.46-1.42 (m, 2H), 1.03 (m, 1H), 0.59-0.56 (m, 2H),0.35-0.31 (m, 2H)

Example 142-Cyclopropylmethyl-5-iodo-7-methyl-2,3-dihydro-isoindol-1-one

To a solution of5-Bromo-7-methyl-2-cyclopropylmethyl-2,3-dihydro-isoindol-1-one (1.0 g,3.56 mmol) in butanol (10 ml),(1R,2R)-N,N′-dimethylcyclohexane-1,2-diamine (204 mg, 1.42 mmol),copper(I) iodide (140 mg, 0.714 mmol) and sodium iodide (1.08 g, 14.3mmol) were added. The resulting mixture was stirred at 120° C.overnight. After cooling, the mixture was diluted with ethyl acetate,washed with water, brine, dried over anhydrous sodium sulphate,filtered, concentrated. Column chromatography (30% EtOAc/Hexanes)provided the title compound (1.07 g, 92%) as a colourless solid. ¹H NMR(300 MHz, CDCl₃): δ 7.65 (s, 1H), 7.59 (s, 1H), 4.42 (s, 2H), 3.46-3.44(d, 2H), 2.70 (s, 3H), 1.04-1.02 (m, 1H), 0.61-0.57 (m, 2H), 0.34-0.31(m, 2H)

Example 155-(1-Benzyl-pyrrolidin-3-ylamino)-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one

3-Amino-1-benzyl-pyrrolidine (57 mg, 0.325 mmol),5-Bromo-7-methyl-2-(4-trifluoromethoxybenzyl)-2,3-dihydro-isoindol-1-one(100 mg, 0.25 mmol), NaO^(t)Bu (168 mg, 1.75 mmol), BINAP (16 mg, 0.025mmol) and Pd₂(dba)₃ (23 mg, 0.025 mmol) were dissolved in anhydroustoluene (5 mL). The mixture was immersed in a 110° C. oil bath. Aftereighteen hours, the reaction was cooled and poured into water andextracted with ethyl acetate. The organic phase was washed with brine,dried over MgSO₄, filtered and concentrated. The compound was purifiedby column chromatography (50% EtOAc/Hexanes) to provide the titlecompound as a yellow gum (87 mg, 70%). ¹H NMR (300 MHz, CDCl₃): δ7.24-7.34 (m, 7H), 7.18 (d, 2H), 6.34 (d, 2H), 4.72 (s, 2H), 4.33 (d,1H), 4.12 (s, 2H), 4.04 (m, 1H), 3.64 (collapsed dd, 2H), 2.75-2.83 (m,2H), 2.66 (s, 3H), 2.58 (dd, 1H), 2.45 (ddd, 1H), 2.32-2.42 (m, 1H),1.67-1.70 (m, 1H).

Example 16.17-Methyl-5-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-2-(4-trifluoromethoxybenzyl)-2,3-dihydro-isoindol-1-one

Methanesulfonic acid5-[7-methyl-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindol-5-yl]-pyridin-3-ylmethylester (36 mg, 0.071 mmol) was dissolved in THF (5 mL). N-Methylpiperazine (24 uL, 0.213 mmol) was added and the mixture stirred at 50°C. for 18 hrs. The mixture was cooled, diluted with water, and extractedwith ethyl acetate. The organics were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated. Columnchromatography (5% 2M NH₃ in MeOH/CH₂Cl₂) provided the title compound(24 mg, 67%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 8.73 (s, 1H),8.56 (s, 1H), 7.86 (s, 1H), 7.42 (d, 2H), 7.37 (d, 2H), 7.19 (d, 2H),4.82 (s, 2H), 4.32 (s, 2H), 3.60 (s, 2H), 2.85 (s, 3H), 2.52-2.42 (br s,8H), 2.30 (s, 3H).

The following compound was prepared in a similar manner:

Example Structure Name Yield 16.2

7-Methyl-5-[6-(4-methyl- piperazin-1-ylmethyl)- pyridin-3-yl]-2-(4-trifluoromethoxy- benzyl)-2,3-dihydro-iso- indol-1-one 48 mg, 80% brownoil NMR 8.78 (s, 1H), 7.85 (s, 1H), 7.50 (d, 1H), 7.40-7.34 (m, 4H),7.20 (d, 2H), 4.81 (s, 2H), 4.32 (s, 2H), 3.73 (s, 2H), 2.84 (s, 3H),2.60-2.52 (br d, 8H), 2.31 (s, 3H)

Example 17.14-{4-[7-Chloro-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindol-5-ylmethyl]-piperidin-1-ylmethyl}-benzonitrile

To a mixture of 4-Cyano-benzyl bromide (12 mg, 0.06 mmol),7-chloro-5-piperidin-4-ylmethyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one(30.0 mg, 0.06 mmol) and potassium carbonate (42 mg, 0.3 mmol) was addedacetonitrile (3.0 mL). The mixture was allowed to stir at roomtemperature overnight. Water (2.0 mL) was added and the product wasextracted with ethyl acetate. The organic layer was washed with water,brine, dried over sodium sulfate, filtered and concentrated. Columnchromatography provided the title compound as a brown oil (39.0 mg,99%). ¹H NMR (300 MHz, CDCl₃): δ 7.60 (d, 2H), 7.27-7.59 (m, 4H),7.17-7.20 (m, 3H), 7.05 (s, 1H), 4.77 (s, 2H), 4.22 (s, 2H), 3.53 (s,2H), 2.80-2.84 (m, 2H), 2.58-2.60 (m, 2H), 1.91 (t, 21, 1.56-1.62 (m,3H), 1.27-1.34 (m, 2H).

The following compounds were prepared in a similar manner:

Example Structure Name Yield 17.2

4-[4-(7-Chloro-2- cyclopropylmethyl-1- oxo-2,3-dihydro-1H-isoindol-5-ylmethyl)- piperidine-1- ylmethyl]- benzonitrile 21.1 mg,82.4%, brown oil NMR 7.59-7.62 (m, 2H), 7.45 (d, 2H), 7.18 (s, 1H), 7.11(s, 1H), 4.43 (s, 2H), 3.53 (s, 2H), 3.46 (d, 2H), 2.81-2.85 (m, 2H),2.60-2.62 (m, 2H), 1.92-1.99 (m, 2H), 1.50-1.64 (m, 3H), 1.27-31.35 (m,2H), 0.98-1.05 (m, 1H), 0.55-0.60 (m, 2H), 0.33-0.35 (m, 2H) 17.3

4-{4-[7-Chloro-2-(4- chloro-benzyl)-1- oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]- piperidin-1- ylmethyl}- benzonitrile 81.8 mg,97.1%, yellow oil NMR 7.58-7.62 (m, 2H), 7.42-7.50 (m, 2H), 7.24-7.32(m, 4H), 7.18 (s, 1H), 7.04 (s, 1H), 4.73 (s, 2H), 4.19 (s, 2H), 3.51(s, 2H), 2.79-2.83 (m, 2H), 2.57-59 (m, 2H), 1.90-1.97 (m, 2H),1.49-1.61 (m, 2H), 1.24-1.37 (m, 3H) 17.4

4-{4-[7-Chloro-2-(4- difluoromethoxy- benzyl)-1-oxo-2,3-dihydro-1H-isoindol- 5-ylmethyl]- piperidin-1- ylmethyl}- benzonitrile35.2 mg, 72.9%, yellow oil NMR 7.59-7.61 (m, 2H), 7.42-7.45 (m, 2H),7.30-7.35 (m, 2H), 7.19 (s, 1H), 7.05-7.11 (m, 3H), 6.26-6.75 (t, 1H),4.75 (s, 2H), 4.21 (s, 2H), 3.52 (s, 2H), 2.79-2.83 (m, 2H), 2.58-2.60(m, 2H), 1.88-1.98 (m, 2H), 1.51-1.62 (m, 3H), 1.25-1.37 (m, 2H) 17.5

4-{4-[7-Chloro-2-(4- ethyl-benzyl)-1- oxo-2,3-dihydro-1H- isoindol-5-yl-methyl]-piperidin-1- ylmethyl}-benzonitrile 16.2 mg, 43.3%, yellow oilNMR 7.59-7.62 (m, 2H), 7.42-7.48 (m, 2H), 7.24-7.28 (m, 2H), 7.16-7.18(m, 3H), 7.02 (s, 1H), 4.74 (s, 2H), 4.19 (s, 2H), 3.52 (s, 2H),2.79-2.83 (m, 2H), 2.57-2.68 (m, 4H), 1.90-1.98 (m, 2H), 1.51-1.61 (m,3H), 1.21-1.36 (m, 5H)

Example 18.14-{4-[7-Chloro-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindol-5-ylmethyl]-piperazin-1-methyl}-nicotinonitrile

4-(piperazin-1-ylmethyl)benzonitrile (30 mg, 0.094 mmol) was dissolvedin dichloromethane (2.0 mL) and7-Chloro-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carbaldehyde(20.0 mg, 0.054 mmol) was added. The mixture was stirred for ten minutesand sodium triacetoxy borohydride (16.1 mg, 0.076 mmol) was added andthe reaction was allowed to stir overnight. The reaction was thendiluted with dichloromethane, washed with saturated sodium bicarbonateand brine, dried over sodium sulfate, filtered and concentrated. Columnchromatography (20% MeOH/EtOAc) provided the title compound as a yellowoil (17.9 mg, 32%). ¹H NMR (300 MHz, CDCl₃): δ 7.60-7.63 (m, 2H),7.34-7.47 (m, 5H), 7.27-7.28 (m, 1H), 7.18-7.21 (m, 2H), 4.78 (m, 2H),4.24 (s, 2H), 3.55-3.57 (m, 4H), 2.48-2.53 (m, 8H).

The following compound was prepared in a similar manner:

Example Structure Name Yield 18.2

3-{3-[1-(7-Chloro-2- cyclopropylmethyl-1-oxo- 2,3-dihydro-1H-isoindol-5- ylmethyl)-piperidin-4-yl]- propyl}- benzonitrile 13 mg, 70.3%, yellowoil NMR 7.41-7.50 (3H), 7.34-7.38 (m, 2H), 4.44 (s, 2H), 3.52 (s, 2H),3.46 (d, 2H), 2.84-2.87 (m, 2H), 2.64 (t, 2H), 1.85-1.98 (m, 3H),1.65-1.68 (m, 4H), 1.26-1.30 (m, 4H), 1.02-1.08 (m, 1H), 0.55-0.61 (m,2H), 0.33- 0.37 (m, 2H)

Example 197-Chloro-2-cyclopropylmethyl-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile

5-Bromo-7-chloro-2-cyclopropylmethyl-2,3-dihydro-isoindol-1-one (360 mg,1.20 mmol) was set stirring in DM (15 mL) under argon and Zn(CN)₂ (154mg, 1.32 mmol) and Pd(PPh₃)₄ (139 mg, 0.12 mmol) were added. Thereaction was stirred at 80° C. for 1.5 hours. The reaction waspartitioned between ethyl acetate and water and the organic layer waswashed with brine and dried over anhydrous Na₂SO₄. The solvent wasremoved under reduced pressure and the product was purified by columnchromatography (40% EtOAc/Hexanes) to afford a yellow solid (142.6 mg,82%). ¹H NMR (300 MHz, CDCl₃): δ 7.53 (s, 2H), 7.36 (d, 2H), 7.22 (s,2H), 4.80 (s, 2H), 4.30 (s, 2H), 2.81 (s, 3H).

Example 207-Trifluoromethyl-5-methoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one

A mixture of7-trifluoromethyl-5-bromo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one(0.060 g, 0.15 mmol), and 30% sodium methoxide-methanol (0.21 mL) inmethanol (4 mL) was stirred at 100° C. for 1 h. Workup and silica gelcolumn chromatography using 30% ethyl acetate in hexane afforded7-trifluoromethyl-5-methoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one(0.043 g, 70%). ¹H NMR (300 MHz, CDCl₃): δ (ppm) 3.88 (s, 3H), 4.25 (s,2H), 4.76 (s, 2H), 7.02 (s, 1H), 7.17 (d, 2H), 7.28 (s, 1H), 7.37 (d,2H).

Example 215,7-Dimethoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1one

To a solution of4-bromo-5,7-Dimethoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1one (0.200 g, 0.45 mmol) in benzene under N2 atmosphere was added2,2′-azobis(2-methyl proponitrile) AIBN (5.0 mg), followed by tributyltin hydride (0.238 mL, 0.9 mmol). The resulting mixture was refluxed inan oil bath for 2 h. The reaction was monitored by GC-MS for thedisappearance of starting material. The reaction mixture was cooled toroom temperature and stirred with potassium fluoride (200 mg) for 45min. The solids were filtered and the filtrate was concentrated. Theresulting material was purified using column chromatography (typically40% ethyl acetate in hexanes) to give5,7-Dimethoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1one(0.106 g, 64%). ¹H NMR (300 MHz, CDCl₃): δ (ppm) 3.82 (s, 3H), 3.95 (s,3H), 4.17 (s, 2H), 4.72 (s, 2H), 6.43 (d, 2H), 7.16 (d, 2H), 7.32 (d,2H). GC-MS: m/z 367 (M)⁺, 349 (M-18)⁺.

Example 22 5,7-Dimethoxy-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1one

To a solution of4-bromo-5,7-Dimethoxy-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-lone(0.100 g, 0.25 mmol) in benzene under N2 atmosphere was added2,2′-azobis(2-methyl proponitrile) AIBN (5.0 mg), followed by tributyltin hydride (0.132 mL, 0.5 mmol). The resulting mixture was refluxed inan oil bath for 2 h. The reaction was monitored by GC-MS for thedisappearance of starting material. The reaction mixture was cooled toroom temperature and stirred with potassium fluoride (200 mg) for 45min. The solids were filtered and the filtrate was concentrated. Theresulting material was purified using column chromatography (typically40% ethyl acetate in hexanes) to give5,7-Dimethoxy-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-lone (0.035 g,44%). ¹H NMR (300 MHz, CDCl₃): δ (ppm) 3.82 (s, 3H), 3.95 (s, 3H), 4.15(s, 2H), 4.69 (s, 2H), 6.43 (d, 2H), 7.25 (m, 4H). GC-MS: m/z 317 (M)⁺,299 (M-18)⁺.

Example 235,7-Dimethoxy-2-[1-(4-chloro-phenyl)-ethyl]-2,3-dihydro-isoindol-1one

To a solution of4-bromo-5,7-Dimethoxy-2-[1-(4-chloro-phenyl)-ethyl]-2,3-dihydro-isoindol-1one(0.112 g, 0.27 mmol) in benzene under N2 atmosphere was added2,2′-azobis(2-methyl proponitrile) AIBN (5.0 mg), followed by tributyltin hydride (0.145 mL, 0.55 mmol). The resulting mixture was refluxed inan oil bath for 2 h. The reaction was monitored by GC-MS for thedisappearance of starting material. The reaction mixture was cooled toroom temperature and stirred with potassium fluoride (200 mg) for 45min. The solids were filtered and the filtrate was concentrated. Theresulting material was purified using column chromatography (typically40% ethyl acetate in hexanes) to give5,7-Dimethoxy-2-[1-(4-chloro-phenyl)-ethyl]-2,3-dihydro-isoindol-1one(0.056 g, 63%). ¹H NMR (300 MHz, CDCl₃): δ (ppm) 1.43 (d, 3H), 3.63 (s,3H), 3.68 (d, 1H), 3.74 (s, 3H), 3.99 (d, 1H), 5.53 (q, 1H), 6.23 (dd,2H), 7.15 (m, 4H). GC-MS: m/z 331 (M)⁺, 316 (M-15)⁺.

1. A compound selected from the group consisting of:7-Chloro-2-[(4,4-difluorocyclohexyl)methyl]-1-oxoisoindoline-5-carbonitrile,7-Chloro-5-[5-(4-hydroxy-piperidin-1-ylmethyl)[1,2,4]oxadiazol-3-yl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one,7-Chloro-5-[5-(4-oxo-piperidin-1-ylmethyl)-[1,2,4]oxadiazol-3-yl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one,7-Chloro-5-[5-(4-fluoro-piperidin-1-ylmethyl)[1,2,4]oxadiazol-3-yl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one,7-Chloro-2-(4,4-difluoro-cyclohexyl-methyl)-5-[5-(4-fluoro-piperidin-1-ylmethyl)-[1,2,4]oxadiazol-3-yl]-2,3-dihydro-isoindol-1-one,2-Cyclopropylmethyl-5-[1-(2-fluorobenzyl)-piperidin-4-ylmethyl]-7-methyl-2,3-dihydro-isoindol-1-one,2-Cyclopropylmethyl-5-[1-(3-fluoro-benzyl)-piperidin-4-ylmethyl]-7-methyl-2,3-dihydro-isoindol-1-one,2-Cyclopropylmethyl-5-[1-(2-methoxy-benzyl)-piperidin-4-ylmethyl]-7-methyl-2,3-dihydro-isoindol-1-one,2-Cyclopropylmethyl-5-[1-(3-methoxy-benzyl)-piperidin-4-ylmethyl]-7-methyl-2,3-dihydro-isoindol-1-one,2-Cyclopropylmethyl-5-[1-(4-methoxy-benzyl)-piperidin-4-ylmethyl]-7-methyl-2,3-dihydro-isoindol-1-one,2-Cyclopropylmethyl-5-[1-(4-fluoro-benzyl)-piperidin-4-ylmethyl]-7-methyl-2,3-dihydro-isoindol-1-one,2-Cyclohexylmethyl-5-[1-(3-fluoro-benzyl)-piperidin-4-ylmethyl]-7-methyl-2,3-dihydro-isoindol-1-one,2-Cyclohexylmethyl-5-[1-(4-fluoro-benzyl)-piperidin-4-ylmethyl]-7-methyl-2,3-dihydro-isoindol-1-one,2-Cyclopropylmethyl-5-[1-(3-fluoro-benzyl)-piperidin-4-ylmethoxy]-7-methyl-2,3-dihydro-isoindol-1-one,2-Cyclopropylmethyl-5-[1-(4-methoxybenzyl)-piperidin-4-ylmethoxy]-7-methyl-2,3-dihydro-isoindol-1-one,5-(1-Benzyl-pyrrolidin-3-ylamino)-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one,4-{4-[7-Chloro-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindol-5-ylmethyl]-piperidin-1-ylmethyl}-benzonitrile,4-[4-(7-Chloro-2-cyclopropylmethyl-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl)-piperidine-1-ylmethyl]-benzonitrile,4-{4-[7-Chloro-2-(4-chloro-benzyl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-piperidin-1-ylmethyl}-benzonitrile,4-{4-[7-Chloro-2-(4-difluoromethoxy-benzyl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-piperidin-1-ylmethyl}-benzonitrile,4-{4-[7-Chloro-2-(4-ethyl-benzyl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-piperidin-1-ylmethyl}-benzonitrile,4-{4-[7-Chloro-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindol-5-ylmethyl]-piperazin-1-methyl}-nicotinonitrile,3-{3-[1-(7-Chloro-2-cyclopropylmethyl-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl)-piperidin-4-yl]-propyl}-benzonitrile,7-Chloro-2-cyclopropylmethyl-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile,5-Fluoro-2-(4-ethyl-benzyl)-7-trifluoromethyl-2,3-dihydro-isoindol-1-one,5,7-Dimethoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one,5,7-Dimethoxy-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one, and5,7-Dimethoxy-2-[1-(4-chloro-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one;or a pharmaceutically acceptable salt, optical isomer, or combinationthereof.
 2. A pharmaceutical composition comprising a compound, apharmaceutically acceptable salt, an optical isomer, or combinationthereof according to claim 1 and a pharmaceutically acceptable carrieror excipient.
 3. A method for the treatment of schizophrenia comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound, a pharmaceutically acceptable salt, an opticalisomer, or combination thereof according to claim
 1. 4. A method for thetreatment of schizophrenia comprising administering to a subject in needthereof a therapeutically effective amount of, a pharmaceuticalcomposition according to claim 2.